P53

This review was inspired by this 300-page book that tells the story of the medical project to unravel the mystery of the vital P53 gene that manages the constant process of cell division, looking for mistakes which if not corrected may lead to cancer. If the mistake cannot be corrected then the P53 gene initiates apoptosis: planned cell suicide. However, if the P53 gene itself is damaged then cancer usually develops, as further bad mistakes will often accumulate. This science author was schooled by some of the original pioneers, who uncovered this mystery, as she systematically reveals in this ZigZag of a convoluted story that slowly exposes how science is really done: by the acceptance of imaginative leaps of discovery and imagination. After 20 years, it became the most studied protein (or its source gene P53) in biomedical research until finally more than 50 percent of human cancer tumors were found to contain a mutation or were missing the P53 gene. AUTHOR'S BIOGRAPHY Sue Armstrong (born 1924) is a British science writer specializing in health and developmental issues. She has written for a wide variety of publications, including New Scientist magazine, UNAIDS, the World Health Organization. For many years she reported on the AIDS pandemic in Africa, Asia and the Caribbean.

Ubiquitin-like proteins (Ubls) confer diverse functions on their target proteins. The modified proteins are involved in various biological processes, including DNA replication, signal transduction, cell cycle control, embryogenesis, cytoskeletal regulation, metabolism, stress response, homeostasis and mRNA processing. Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system. Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized. In this review, we focus on cellular processes involving human Ubls and their targets. We review current progress in targeting these modifiers for drug design strategies.

Background and Aim: Squamous cell carcinoma (SCC) is the most common form of carcinoma in cattle. Histopathological grading systems have been utilized over several decades for estimating the malignancy of cattle SCCs. This study aimed to detect p53 and Mdm2 expression in different SCC cases in cattle and correlate their expression with the SCC histopathological grading.

Materials and Methods: Cattle SCC cases were collected at the Veterinary Teaching Hospital in Nineveh. The SCC grading system categorized the cases histologically based on their differentiation grade into three groups: Well, moderately, and poorly differentiated. The SCC cases were subsequently verified for p53 and Mdm2 immunoexpression.

Results: Fourteen of 16 examined cattle SCC samples tested positive for p53 expression. Moreover, 15 out of the 16 SCC samples tested positive for Mdm2 expression. The increased immunoreactivity of both p53 and Mdm2 was associated with a poor histological grading of the cattle SCC. There is a positive correlation between the nuclear expression of p53 and Mdm2, and the degree of differentiation and the number of mitotic figures in the examined cattle SCC samples.

Conclusion: Our results demonstrate an increased p53 and Mdm2 expression in cattle SCC cases characterized by poor histopathological grading, thus suggesting an essential role of these molecules in the development of moderately and poorly differentiated SCC in cattle.

The immunohistochemical expression of proliferating cell nuclear antigen (PCNA) and p53 was investigated in 9 cases of epithelial dysplasia and 38 cases of squamous cell carcinoma of the oral cavity. The intensity of immunoreactivity for each marker was assessed using a semiquantitative grading system, and was correlated with tumor differentiation, nuclear atypia and the patterns of invasive margins in the underlying connective tissue. PCNA expression, in dysplastic epithelium, was observed in the suprabasal and lower spinous layers; and the labeling grade and intensity of staining increased along the degree of cellular atypia. In 2 cases of dysplasia, weak positive immunoreactivity for p53 could be seen in a few isolated cells of the basal layer. In the squamous cell carcinoma, PCNA expression was correlated with the degree of tumor differentiation and nuclear atypia in well and moderately differentiated carcinoma, but not with the invasive pattern of tumor growth. Immunoreactivity for p53 was positive in 30 cases and showed a distribution pattern very similar to PCNA but with fewer positive cells. Three distinct categories of expression for PCNA and p53 were observed, among them a combination of intense reactivity for both markers was indicative of poor differentiation, higher nuclear atypia and more invasive growth of tumor cells.

Endometriosis associated ovarian carcinoma (EAOC) is currently receiving attention due to the controversy about its biological behavior. It is not clear whether tumors with demonstrable transition of benign to malignant lining of ovarian endometriosis differ from ovarian carcinomas with associated endometriosis in cases where direct transition is not evident. This study examined the association between the relationship of endometriosis and ovarian cancer and histopathologic characteristics, p53 status and outcome. Methods 140 patients with EAOC with available tissue met the inclusion criteria. Patients were categorized as EAOC type I when direct transition of benign to malignant lining was identified in ovarian endometriosis and EAOC type II when ovarian endometriosis was present but no direct transition to carcinoma was demonstrated. Age, histologic type, FIGO stage and disease free survival were compared between the groups. P53 status was determined by immunohistochemistry using tissue microarray. Results Seventy one (51.07%) patients had EAOC type I while 69 (49.6%) patients had EAOC type II. There was a significant difference in cell type composition between the groups. The most common histologic type in EAOC type I was endometrioid carcinoma (35, 49.3%) followed by clear cell carcinoma (29, 40.8%) and serous carcinoma (7, 9.9%). The most common histologic type in EAOC type II was serous carcinoma (35, 50.7%) followed by endometrioid carcinoma (20, 29%), clear cell carcinoma (9, 13%) and mucinous carcinoma (5, 7.2%), P < 0.001. Of 140 patients with EAOC, 139 tumor tissue specimens were identified on the TMAs. Mutant p53, either overexpressed or null phenotype, was detected in 16/71 (22.5%) patients with EAOC type I vs. 33/68 (48.5%) patients with type II, P=0.003. However when p53 status was compared in the two groups by tumor histology and grade, there was no significant difference between EAOC type and P53 status. EAOC type I cases were more likely to present at a lower stage. DFS was not associated with EAOC type but was significantly decreased in cases with mutant p53. Conclusion In this single institution cohort, the outcome of patients with ovarian carcinoma was related to the histological type and stage. However, the type of EAOC was not independently predictive of outcome. Biological differences such as in p53 status, stage at diagnosis and outcome reflect the higher proportion of serous and high grade endometrioid carcinoma in EAOC type II.

The p53 tumor suppressor gene and gene product are among the most diverse and complex molecules involved in cellular functions. Genetic alterations within the p53 gene have been shown to have a direct correlation with cancer development and have been shown to occur in nearly 50% of all cancers. p53 mutations are particularly common in skin cancers and UV irradiation has been shown to be a primary cause of specific 'signature' mutations that can result in oncogenic transformation. There are certain 'hot-spots' in the p53 gene where mutations are commonly found that result in a mutated dipyrimidine site. This review discusses the role of p53 from normal function and its dysfunction in pre-cancerous lesions and nonmelanoma skin cancers. Additionally, special situations are explored, such as Li-Fraumeni syndrome in which there is an inherited p53 mutation, and the consequences of immune suppression on p53 mutations and the resulting increase in non-melanoma skin cancer in these patients. Published by Elsevier Inc.

TET1 protein is to suppress cancer invasion and metastasis in prostate and breast cancer while EZH2, a polycomb group protein, has been identified as an oncogene in many types of cancers including gastric cancer. Here we report that there is an inverse relation of the expression pattern of TET1 and EZH2 in both normal gastric mucosa and gastric cancer. In gastric mucosa, EZH2 is selectively expressed in the proliferating neck cells while TET1 and 5-hydroxymethyl-cytosine (5-hmc) exhibit very low expression in the neck cells. In contrast, TET1 and 5-hmc expression is high in gastric glandular epithelium while EZH2 expression is absent in this cell population. On the other hand, in proliferating Ki67-positive gastric cancer cells, EZH2 is highly expressed while TET1 and 5-hmc expression is significantly down-regulated. When the mouse homologue of human TET1 protein Tet1 is overexpressed in a gastric cancer cell line MGC-803, we observed the dramatically down-regulation of EZH2 in one-third of the Tet1 overexpressed cells. In addition, Tet1 overexpressing cells also lost the H3K27 trimethylation mark and the cell proliferation protein Ki67. Furthermore, Tet1 overexpression induced p53 tumor suppressor protein. The increase of p53 protein level is accompanied by the phosphorylation of p53 by activated DNA-PK. Together, these results suggested a mechanism by which TET1 suppresses cancer formation by coupling DNA demethylation with DNA-PK activation of p53 and suppression of oncogenic protein EZH2. Conversely, loss of TET1 and 5-hmc expression might contribute to EZH2 up-regulation during gastric cancer development.

Background: Differentiation of urothelial hyperplasia, dysplasia and carcinoma in situ (CIS) may pose diagnostic difficulties. We aim to evaluate the role of CK20, p53 and p63 in differentiation of such lesions. Methods: we evaluate these markers in 213 cases of bladder lesions (14 hyperplasia, 7 dysplasia, 5 CIS, 25 noninvasive and 162 invasive urothelial carcinoma) in a retrospective study on sections from formalin-fixed, paraffin-embedded blocks. Cytoplasmic staining considered for CK20 and nuclear staining for p53 and p63. Results: CK20 was expressed in 14 out of 14 hyperplasia (4 strong, 7 moderate, 3 weak), in 7 out of 7 dysplasia (4 strong , 3 moderate), in 5 out of 5 CIS, in 19 out of 25 noninvasive carcinoma; strong in 11 (7 low grade, 4 high grade), moderate in 7 (5 low grade, 2 high grade), and weak in 1 case of low grade, in 136 out of 162 invasive carcinoma; strong in 46 (22 grade II, 24 grade III), moderate in 71 (2 grade I, 58 grade II, 11 grade III), and weak in 19 (2 grade I, 15 grade II, 2 grade III), no expression in 2 cases of grade IV. p53 was expressed in 7 out of 14 hyperplasia (weak in all cases), in 7 out of 7 dysplasia (5 strong, 2 moderate), in 5 out of 5 CIS (strong in all cases), in 20 out of 25 noninvasive carcinoma (8 strong, 9 moderate, 3 weak), in 135 out of 162 invasive carcinoma (34 strong, 73 moderate, 28 weak). p63 was expressed in 14 out of 14 hyperplasia, in 7 out of 7 dysplasia, in 4 out of 5 CIS, in 25 out of 25 noninvasive carcinoma, and in 134 out of 162 invasive carcinoma (28 strong, 63 moderate, 43 weak). CK20 was insignificant in noninvasive and significant in invasive carcinoma, while p53 and p63 were significant in noninvasive and invasive carcinoma. Conclusion: CK20, p53 and p63 are useful in differentiation of different bladder lesions.

This review addresses the significance of the expression of proliferating cell nuclear antigen (PCNA), p53 and some heat shock proteins (Hsps) in prostate carcinoma (PC). In fact, PCNA and p53 are two widely discussed tools in PC diagnosis, mainly because of the controversy regarding the significance of their expression during prostate cancer development and progression. At the same time, only few studies have shown the potential role of Hsps in carcinogenesis and their overexpression in pre-neoplastic and neoplastic lesions of the prostate. We briefly describe the physiological roles of Hsps in normal cells, and the significance of their immunohistochemical detection in PC as well as in pre-cancerous lesions of the prostate. We will also discuss the possible functional interactions of these molecules in both dysplastic and neoplastic cells.

p53 Tumor suppressor gene encodes for a critical cellular protein that regulate the integrity of the cell and can induce cell cycle arrest and/or apoptosis upon cellular stresses of several origins, including chemotherapeutics. Loss of p53 function occurs in an estimated 50% of all cancers by mutations and deletions while in the presence of wild-type p53 alleles other mechanisms may affect the expression and activity of p53. Alternative mechanisms include methylation of the promoter of p53, deletion or epigenetic inactivation of the p53-positive regulator p14/ARF, elevated expression of the p53 regulators murine double minute 2 (MDM2) and MDMX, or alteration of upstream regulators of p53 such as the kinase ATM. MDM2 is a p53 E3 ubiquitin ligase that mediates the ubiquitin-dependent degradation of p53 while p14/ARF is a small MDM2-binding protein that controls the activity of MDM2 by displacing p53 and preventing its degradation. MDMX antagonize p53-dependent transcriptional control by interfering with p53 transactivation function. The understanding of the key role of p53 inactivation in cancer development generated considerable interest in developing compounds that are capable of restoring the p53 functions. Several patents have been issued on such compounds. Adenovirus-based p53 gene therapy as well as small molecules such as PRIMA that can restore the transcriptional transactivation function to mutant p53, or NUTLIN and RITA that interfere with MDM2-directed p53 degradation, have tested in a preclinical setting and some of these approaches are currently in clinical development.

p53 has a determinant role in cancer prevention and is among the most studied proteins in the world. The majority of studies devoted to this protein are carried out in cell lines because they are easy to use and have naturally emerged as the main research tool in laboratories. However, the p53 pathway is commonly deregulated in cancer cells, from which the experimental cell lines are generally derived. The fact that the pathway is deregulated challenges the relevance of using cancer-derived cell lines to study wild-type p53 activities, or, in a broader sense, to study any normal cellular process. In the present article, we identify and discuss a number of limitations of cell lines using examples related to p53. Finally, we point out the general limitations of cell lines and propose solutions as alternatives to these cells.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and one of the prominent causes of cancer mortality, leading to approximately 780,000 deaths per year worldwide. Down-regulation of microRNA-125b (miR-125b) is a prognostic indicator in HCC patients. Conversely, over-expression of miR-125b in HCC cells induces cell cycle arrest, inhibits proliferation, migration and invasion. Extracellular vesicles (EVs) function as intercellular messengers transferring proteins, RNAs, DNAs, carbohydrates, and lipids. Since EVs protect their cargo from degradation, delivery of therapeutic bioactive molecules, in particular miRNAs, through EVs represents an innovative avenue for cancer therapy. In this study, we evaluated a replacement strategy for the treatment of HCC via delivery of EVs secreted from human adipose tissue-derived mesenchymal stromal/medicinal signaling cells (ASCs) genetically modified with a lentiviral vector expressing miR-125b with a specific ExoMotif sequence tag to enhance the loading into extracellular vesicles. In particular, we determined that the delivery of miR-125b-loaded EVs produced in engineered ASCs specifically reduces HCC cell proliferation in vitro modulating a series of miR-125b targets, which belong to the p53 signaling pathway. This proof-of-concept study supports the development of innovative therapeutic strategies for HCC via EV-mediated miRNA delivery.

Scan to discover online Background & Objective: Urothelial carcinoma is the seventh most common cancer in the world. The histological classification of papillary carcinoma is one of the most important determinants for its prognosis. Sometimes there is an overlap in the extent of the tumor, and the accurate microscopic diagnosis of the tumor is not always easy. The aim of this study was to evaluate P53 and CK20 immunohistochemical markers in comparison with morphologic findings in low-and high-grade urothelial carcinomas. Methods: For this descriptive study, urinary bladder samples were collected from 50 cancer patients who had undergone biopsy and surgery in Shohaday-e Tajrish Hospital of Tehran, Iran, during the years 2015-2016. P53 and CK20 were studied, and the demographic and histopathological characteristics of the tumor were also analysed. Results: The mean age of patients enrolled in this study (48 males and 2 females) was 65.8±11.9. Twenty-five cases presented with low-grade and 25 cases presented with high-grade papillary urothelial carcinomas. Sensitivity, specificity, and positive and negative predictive values for P53 were 48%, 80%, 70.5%, and 60.6%, respectively, while the same values for CK20 were 44%, 92%, 84.6%, and 62.2%, respectively. Immunohistochemical results were also positively correlated with the extent of the tumor. Conclusion: Based on the results, P53 and CK20 may serve as specific markers for diagnosis of low-and high-grade papillary urothelial carcinoma but not sensitive. P53 and ck20 staining have also a high specificity as 80% and 92% and low sensitivity compared to the low and high morphology of papillary carcinoma, thus their positive and their staining intensity are valuable for diagnosis, but their negative results are not determinant.

Abstract Cellular senescence is an in vivo and in vitro
phenomenon, accompanied by physiological changes
including cessation of division and disturbances of
organelle structure and function. Review of the literature
was undertaken to determine whether there is evidence
that whole organism aging and cell senescence share a
common initiation pathway. In vivo aged cells of
different lineages, including aged T lymphocytes, show
high expression of the INK4A-p16 gene. In cell culture
when telomeres are shortened past a key length or
state, the Arf/Ink gene system (p16/p14 humans,
p16/p19 mice) switches on and activates p53, which
suppresses further cell division. The p53 gene is a key
tumor suppressor and its deletion or mutation allows
cancerous growth. The switching on of p53 also causes
changes in fatty acid metabolism, especially downregulation
of both fatty acid synthase and stearoyl-CoA
(delta-9) desaturase. The co-suppression of these genes
together with enhanced uptake of extracellular fatty
acids, leads to raised levels of cellular palmitate and
induction of either apoptosis or senescence. In senescent
cells, the fatty acid composition of the cellular membranes
alters and leads to changes in both structure and
function of organelles, especially mitochondria. Animal
models of accelerated aging exhibit repression of
stearoyl-CoA desaturase activity while anti-aging
calorie restriction stimulates the same enzyme system.
It is concluded that aging in cells and whole organisms
share a common initiation pathway and that cellular
senescence is protective against cancer. Healthy longevity
is likely to be most enhanced by factors that
actively suppress excessive cell division.
Keywords Aging . p53 . Ink4a . Arf . p16 . fasn .
Stearoyl-Coenzyme A-desaturase .
Stearoyl-CoA-desaturase . Delta-9 desaturase .
Telomere . Senescence . Calorie restriction . Palmitate .
Palmitic acid . Cancer

Silibinin is known for its hepatoprotective, anti-inflammatory, and anti-carcinogenic effects. We found that silibinin exhibited a protective effect against chemotherapeutic reagent mitomycin C-induced cell death in A375-S2 cells in a p53-dependent manner, which contradicted the findings of previous studies investigating the anti-neoplastic activity of silibinin and developing silibinin as a potential anti-neoplastic drug in clinical therapy. Mitomycin C administration triggered a time-and dose-dependent cell death in A375-S2 cells. Apoptotic morphology, DNA fragmentation, and caspase-3 activation demonstrated that the major cause of A375-S2 cell death by mitomycin C was apoptosis. This was associated with a marked increase of p53 level and changes in mitochondria associated proteins. However, preincubation with silibinin prior to mitomycin C treatment substantially suppressed cell apoptosis, attenuated the change of p53 and Bcl-2 expressions, blocked the translocation of Bax to mitochondrial outer membrane, and ameliorated the loss of mitochondrial membrane potential, but mitomycin C stimuli led to few changes in the protein levels of caspase 8, Fas ligand, and Fas-associated death domain protein, indicating that silibinin protected cells from mitomycin C-induced apoptosis mainly via suppressing the mitochondria-mediated intrinsic apoptosis pathway, but not in an extrinsic manner.

Senolytics inhibiting the accumulation of senescent cells in the tissues of the elderly, certainly help to counteract the development of age-related pathology. However senolytics should not be used as monotherapy, but in combination with loss replacement methods.  One way to compensate  losses may be by cloning basic progenitor cells using a method of “Conditionally reprogrammed (conditionally immortalized) cells (CRC). So far, this technology has been successfully tested only for in vitro experiments. However, there are prerequisites to use this technology in vivo.  Effect of induced cellular proliferation, concomitant with the amelioration of senescent phenotype by ROCK inhibition was observed in vivo as evidenced by the facilitated cutaneous wound healing. Since one of the factors contributing to the rejuvenation of cells with the formation of (CRC) is Δ133p53α (a natural p53 isoform),  it would be interesting to test its effect in vivo in combination with ROCK inhibitor on  prolongation of healthy life.

Genomic regulation and functional significance of PVT‐1 gene locus, in the MYC‐driven cancers, has remained enigmatic ever since its discovery. With the present study, an attempt is made to establish that cellular AATF genome encoded miR‐2909 RNomics pathway involving crucial genes coding for KLF4, Deptor, mTORC1, STAT3, and p53
has the inherent capacity to ensure sustained co‐amplification of PVT‐1 gene locus together with c‐Myc gene. Based upon these results, we propose thatmiR‐2909 RNomics pathway may play a crucial role in the regulation of tumorigenic PVT‐1 gene locus.

A B S T R A C T Although chemicals are usually present in the environment in complex mixtures, ecotoxicological risk assessments often rely on data from single exposures to contaminants. The present study aimed at examining the effects of two ubiquitous endocrine disrupting chemicals (EDCs), 17α-ethynilestradiol (EE 2) and tributyltin (TBT), single and combined, in zebrafish (Danio rerio) reproduction and embryonic development, and to investigate the impact on DNA repair molecular pathways. Chronic life-cycle exposure to environmental relevant concentrations of both EDCs led to significant effects on reproduction and embryonic development. TBT exposure at 50 ng/L impacted the percentage of fertilized eggs. EE 2 exposure at 0.75 and 1.75 ng/L and the mixture treatments (0.75 and 1.75 ng/L EE 2 plus 50 ng/L TBT) led to a sex bias towards females. Furthermore, EE 2 exposure at 1.75 ng/L and the mixture of EE 2 (1.75 ng/L) and TBT (50 ng/L) impaired embryonic development. The study of DNA repair pathways indicated that EE 2 and TBT, single and combined, significantly modulated the expression levels of key DNA repair genes in male gonads, such as xpc nucleotide excision repair (NER) pathway gene as well as the tumor suppressor p53, its target effectors, i.e. p21, gadd45α and bax, and p53 key regulator (mdm2). The observed impact in the transcription of these genes supports the hypothesis of an effect of EE 2 , TBT, and their combined mixtures, on DNA repair pathways, thus suggesting that impairment of embryonic development of F 2 generation could be linked to the disruption of DNA repair processes in the gonads of individuals from the parental generation. Taken together, these findings contribute to a better understanding of the impact of mixtures of the ubiquitous contaminants EE 2 and TBT, strongly supporting the inclusion of embryonic development and gene expression studies in the screening of endocrine disruption in wildlife.

ABSTRACT:

Background. The purpose of this study was to determine
whether pretreatment 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET/CT) volume-based parameters, such as metabolic tumor volume and total lesion glycolysis, add more prognostic information in patients with oropharyngeal squamous cell carcinoma (SCC).

Methods. The subjects were 47 patients with oropharyngeal SCC who underwent 18F-FDG PET/CT before any treatment and followed by definitive therapy. PET parameters (metabolic tumor volume and total lesion glycolysis) and tumor p16/p53 status were evaluated retrospectively.Univariate and multivariate analyses were performed for disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS).

Results. All volume-based PET parameters were found to be significant prognostic factors for DFS, DSS, and OS in univariate analysis. In multivariate analysis, only metabolic tumor volume for total tumor lesions (cutoff 65) retained an independent association with DFS, DSS, and OS.

Conclusion. Metabolic tumor volume for total tumor lesions may be a predictive marker for survival outcomes in patients with oropharyngeal SCC with known p16/p53 status.

Chronic lung diseases in older people due to age-related changes are more severe and often cause death. Currently available drugs are not enough to successfully treat these age-related diseases. Additional tissue rejuvenation measures are needed to increase the body's ability to regenerate lung tissue.
One of the ways to achieve this goal can be the technology of conditional reprogramming of cells. So far, this technology has been successfully tested only for in vitro experiments. However, there are prerequisites to use this technology in vivo and this review focuses on the rationale for this approach based on available developments in this direction.
Key words: rejuvenation, senolytics, ROCK inhibitors, conditionally reprogrammed cells, p53 isoform

The BRAF(V600E) mutation is found in approximately 40% of papillary thyroid cancers (PTC). Mice with thyroid-specific expression of Braf(V600E) (TPO-Braf(V600E)) develop PTC rapidly with high levels of serum thyroid-stimulating hormone (TSH). It is unclear to what extent the elevated TSH contributes to tumor progression. To investigate the progression of Braf(V600E)-induced PTC (BVE-PTC) under normal TSH, we transplanted BVE-PTC tumors subcutaneously into nude and TPO-Braf(WT) mice. Regression of the transplanted tumors was observed in both nude and TPO-Braf(WT) mice. They were surrounded by heavy lymphocyte infiltration and oncogene-induced senescence (OIS) was demonstrated by strong β-gal staining and absence of Ki-67 expression. In contrast, BVE-PTC transplants continued to grow when transplanted into TPO-Braf(V600E) mice. The expression of Trp53 was increased in tumor transplants undergoing OIS. Trp53 inactivation reversed OIS and enabled tumor transplants to grow in nude mice with characteristic cell morphology of anaplastic thyroid cancer (ATC). PTC-to-ATC transformation was also observed in primary BVE-PTC tumors. ATC cells derived from Trp53 knockout tumors had increased PI3K/AKT signaling and became resistant to Braf(V600E) inhibitor PLX4720, which could be overcome by combined treatment of PI3K inhibitor LY294002 and PLX4720. In conclusion, BVE-PTC progression could be contained via p53-dependent OIS and TSH is a major disruptor of this balance. Simultaneous targeting of both MAPK and PI3K/AKT pathways offer a better therapeutic outcome against ATC. The current study reinforces the importance of rigorous control of serum TSH in PTC patients.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) and antioxidants opened the way for many effective therapeutic experiments against damaged organs like kidneys. Nephrotoxicity is the main complication of chemotherapeutic drugs. Therefore, the present study aimed to investigate the efficacy of BM-MSCs and hesperidin to treat cisplatin-induced nephrotoxicity in rats. Fifty rats were divided into five equal groups of 10 each. Group-I served as a control group, group-II received a single dose of cisplatin (7.5 mg/kg) intraperitoneally to induce nephrotoxicity, group-III received a daily dose of hesperidin (40 mg/kg) orally for four weeks, and on the 5th day cisplatin was administered an hour before hesperidin administration. Group-IV consisted of cisplatin-treated rats that were intravenously injected with 1х106 BM-MSCs cells/rat once per week. Group V contained cisplatin-treated rats that received a combination of hesperidin and BM-MSCs with the same dosage regimes. After four weeks, serum and kidney samples were collected for biochemical, histological, and immunohistochemical examinations were performed. Cisplatin administered rats showed deteriorated biochemical parameters and severe degenerative changes in renal tissue. Both single and combined hesperidin and BM-MSCs treatments restored the renal biochemical parameters. Histologically, the renal tissues significantly improved in the BM-MSCs treated group in comparison with the hesperidin treated group. Moreover, combined treatment (i.e., group V) showed complete restoration of the normal architecture in the renal tissue. Our data suggest that the combined treatment of BM-MSCs and hesperidin has a potent renoprotective efficacy against cisplatin-induced nephrotoxicity rather than the single treatment

Background: Tumor progression and tumor response to anticancer therapies may be affected by activation of oncogenic pathways such as the antioxidant one induced by NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor and the pathways modified by deregulation of oncosuppressor p53. Often, oncogenic pathways may crosstalk between them increasing tumor progression and resistance to anticancer therapies. Therefore, understanding that interplay is critical to improve cancer cell response to therapies. In this study we aimed at evaluating NRF2 and p53 in several cancer cell lines carrying different endogenous p53 status, using a novel curcumin compound since curcumin has been shown to target both NRF2 and p53 and have anti-tumor activity. Methods: We performed biochemical and molecular studies by using pharmacologic of genetic inhibition of NRF2 to evaluate the effect of curcumin compound in cancer cell lines of different tumor types bearing wild-type (wt) p53, mutant (mut) p53 or p53 null status. Results: We found that the curcumin compound induced a certain degree of cell death in all tested cancer cell lines, independently of the p53 status. At molecular level, the curcumin compound induced NRF2 activation, mutp53 degradation and/or wtp53 activation. Pharmacologic or genetic NRF2 inhibition further increased the curcumin-induced cell death in both mutp53-and wtp53-carrying cancer cell lines while it did not increase cell death in p53 null cells, suggesting a cytoprotective role for NRF2 and a critical role for functional p53 to achieve an efficient cancer cell response to therapy.

Graphical Abstract Highlights d CEP-1 cooperates with HIM-5 to ensure meiotic crossover formation d CEP-1 and HIM-5 promote induction of programmed double-strand breaks d CEP-1 and HIM-5 ensure DSB repair fidelity by antagonizing NHEJ activity

Introduction: Human hematopoietic stem cells (hHSCs) have been used for transplantation
in hematologic failures. Because the number of hHSCs per cord blood unit is limited, the
expansion of these cells is important for clinical application. It has been reported that cytokines
and feeder layer provide a perspective to in vitro expansion of hHSCs. In this regard, cord blood
CD34+ cells expanded after co-culture with adipose-derived stem cells (ADSCs) feeder layer
and cytokine conditions were analyzed in terms of apoptosis and the expression level of p53, a
tumor suppressor gene.
Methods: Three cultures of cord blood CD34+ cells were prepared ex-vivo for 7 days, including
cytokines stem cell factor (SCF), thrombopoietin (TPO), and fetal liver tyrosine kinase 3 ligand
(Flt3L) with ADSCs feeder layer, cytokines without feeder layer, and a culture on micro porous
membrane with cytokines. Apoptosis rate and the expression level of P53 gene in all groups
were analyzed by real-time PCR.
Results: The data showed that p53 expression and apoptosis rate in CD34+ fresh cells were
higher than other culture systems. P53 gene expression in the expanded cells at both cytokine
cultures with and without ADSCs feeder layer decreased, but it was lower than other culture
systems at co-culture system with cytokines (P < 0.05). Apoptosis rate in expanded cord blood
CD34+ with feeder layer was significantly lower than the group without ADSCs feeder layer.
Conclusion: It could be concluded that direct culture of CD34+on feeder layer ADSCs affects
the expansion of HSCs.

Oral squamous cell carcinoma (OSCC) represents 95% of all forms of head and neck cancer, and over the last decade its incidence has increased by 50%. Oral carcinogenesis is a multistage process, which simultaneously involves precancerous lesions, invasion and metastasis. Degradation of the cell cycle and the proliferation of malignant cells results in the loss of control mechanisms that ensure the normal function of tissues. The aim of the current review is to present the histopathological features of OSCC, including potentially malignant changes, the international classification of tumors, the tumor invasion front and tumor biomarkers (Ki-67, p53, homeobox genes and collagen type IV), as well as the tumor microenvironment and function of cancer-associated fibroblasts in the most common type of oral cancer that is encountered by dental surgeons. In OSCC, associations have been identified between the proliferation, basal lamina degradation and connective tissue modulation. Therefore, the comparison of these factors with the survival time of OSCC patients from the histopathological diagnosis is of interest

Geldanamycin (GA) is a specific inhibitor of the 90 kDs heat shock protein (Hsp90) in the cytoplasm of mammalian cells, which binds directly to Hsp90 and promotes proteolytic degradation of its client proteins. As an antitumor drug, GA antagonizes the protecting effects of Hsp90 on cell survival, while its mechanisms remain unclear. Here, we show that GA induces apoptosis in a human neuroblastoma cell line, SH-SY5Y. Treatment of the cells with all trans retinoic acid (RA) generates a neuron-like, morphological change of differentiation, and results in the activation of ERK and Akt pathways, an inhibition of the nuclear translocation of p53 induced by GA, and induces higher resistance to the GAinduced apoptosis. These results provide the first evidence for the requirement of p53 nucleation in SH-SY5Y cells to counteract GA in neuron survival.

Locus-specific databases (LSDBs) are curated compilations of sequence variants in genes associated with disease and have been invaluable tools for both basic and clinical research. These databases contain extensive information provided by the literature and benefit from manual curation by experts. Cancer genome sequencing projects have generated an explosion of data that are stored directly in centralized databases, thus possibly alleviating the need to develop independent LSDBs. A single cancer genome contains several thousand somatic mutations. However, only a handful of these mutations are truly oncogenic and identifying them remains a challenge. However, we can expect that this increase in data and the development of novel biocuration algorithms will ultimately result in more accurate curation and the release of stable sets of data. Using the evolution and content of the TP53 LSDB as a paradigm, it is possible to draw a model of gene mutation analysis covering initial descriptions, the accumulation and organization of knowledge in databases, and the use of this knowledge in clinical practice. It is also possible to make several assumptions on the future of LSDBs and how centralized databases could change the accessibility of data, with interfaces optimized for different types of users and adapted to the specificity of each region of the genome, coding or noncoding, associated with tumor development.

p53 is a master transcription factor that prevents neoplasia and genomic instability. It is an important target for anticancer drug design. Understanding the molecular mechanisms behind its transcriptional activities in normal cells is a prerequisite to further understand the deregulation effected by mutant p53 in cancerous cells. Currently, how p53 coordinates transcription programs in response to stress remains unclear. One theory proposes that stresses induce pre-binding events that direct p53 to bind to specific response elements, whereas a second posits that, in response to stress, p53 binds most response elements and post-binding events then regulate transcription initiation. It is critical to establish the relevance of both theories and investigate whether stresses induce specific p53-binding patterns correlated with effector gene induction. Using unique in cellulo genomic footprinting experiments, we studied p53 binding to the five response elements of p21 in response to stresses and monitored p21 mRNA variant transcription. We show clear footprints of p53 bound to response elements in living cells and reveal that the binding of p53 to response elements is transient, subject to dynamic changes during stress responses, and influenced by response element pentamer orientations. We show further that stresses lead to specific p53-binding patterns correlated with particular p21 mRNA variant transcription profiles and that p53 binding is necessary but not sufficient to induce p21 transcription. Our results indicate that pre-and post-binding events act together to regulate adapted stress responses; this paves the way to the unification of pre-and post-binding event theories. [Cancer Res 2009;69(21):8463-71]

Ovarian cancer happens as the result of change in gene and molecular metabolites. Because of chemotherapy side effects in cancer treatment such as drug resistance, using of complementary therapy with herbal and their derivatives is increased. This study evaluates anti-tumor effects of vitexin on AHRI, p53 and Kras genes expression by Real time PCR. Also metabolite changes due to these variations are measured by 1D NOESY, 1 HNMR. SKOV3 cells treated whit different concentrations of vitexin and determined IC50 by MTT assay. The IC50 was measured as 520µg /ml. Then RNA extracting and building of cDNA done to determine level of genes expression changes. Metabolites extracted by water, chloroformed and methanol and lyophilized samples evaluated by 1HNMR. The expression of AHRI and p53 tumor suppressor genes in the treated cells increased by 1.93 and 1.76 times, respectively, and the expression of Kras oncogene gene decreased by 0.23 times. Maximum changes in metabolites pathways observed in Aminoacyl-tRNA biosynthesis, Biotin, cysteine, methionine, branch amino acids, lysine metabolism, and steroids biosynthesis. Vitexin shows its anti-tumor effects by targeting of several biochemical pathways and reload of metabolites by change in genes which have roll in ovarian cancer. So to confirm this study more evaluations in pathway signaling is needed.

Elephants are large-brained, social mammals with a long lifespan. Studies of elephants can provide insight into the aging process, which may be relevant to understanding diseases that affect elderly humans because of their shared characteristics that have arisen through independent evolution. Elephants become sexually mature at 12 to 14 years of age and are known to live into, and past, their 7 th decade of life. Because of their relatively long lifespans, elephants may have evolved mechanisms to counter age-associated morbidities, such as cancer and cognitive decline. Elephants rely heavily on their memory, and engage in multiple levels of competitive and collaborative relationships because they live in a fission-fusion system. Female matrilineal relatives and dependent offspring form tight family units led by an older-aged matriarch, who serves as the primary repository for social and ecological knowledge in the herd. Similar to humans, elephants demonstrate a dependence on social bonds, memory, and cognition to navigate their environment, behaviors that might be associated with specializations of brain anatomy. Compared with other mammals, the elephant hippocampus is proportionally smaller, whereas the temporal lobe is disproportionately large and expands laterally. The elephant cerebellum is also relatively enlarged, and the cerebral cortex is highly convoluted with numerous gyral folds, more than in humans. Last, an interesting characteristic unique to elephants is the presence of at least 20 copies of the TP53 tumor suppressor gene . Humans have only a single copy. TP53 encodes for the p53 protein, which is known to orchestrate cellular response to DNA damage. The effects of these multiple copies of TP53 are still being investigated, but it may be to protect elephants against multiple age-related diseases. For these reasons, among others, studies of elephants would be highly informative for aging research. Elephants present an underappreciated opportunity to explore further common principles of aging in a large-brained mammal with extended longevity. Such research can contribute to contextualizing our knowledge of age-associated morbidities in humans.

Chemotherapy is central to current treatment modality especially for advanced and metastatic colorectal and breast cancers. Targeting the key molecular events of the neoplastic cells may open a possibility to treat cancer. Although some improvements in understanding of col-orectal and breast cancer treatment have been recorded, the involvement of glutathione (GSH) and dependency of p53 status on the modulation of GSH-mediated treatment efficacy have been largely overlooked. Herein, we tried to decipher the underlying mechanism of the action of Mn-N-(2-hydroxyacetophenone) glycinate (MnNG) against differential p53 status bearing Hct116, MCF-7, and MDA-MB-468 cells on the backdrop of intracellular GSH level and reveal the role of p53 status in modulating GSH-de-pendant abrogation of MnNG-induced apoptosis in these cancer cells. Present study discloses that MnNG targets specifically wild-type-p53 expressing Hct116 and MCF-7 cells by significantly depleting both cytosolic, mitochon-drial GSH, and modulating nuclear GSH through Glu-tathione reductase and Glutamate-cysteine ligase depletion that may in turn induce p53-mediated intrinsic apoptosis in them. Thus GSH addition abrogates p53-mediated apop-tosis in wild-type-p53 expressing cells. GSH addition also overrides MnNG-induced modulation of phase II detoxi-fying parameters in them. However, GSH addition partially replenishes the down-regulated or modulated GSH pool in cytosol, mitochondria, and nucleus, and relatively abrogates MnNG-induced intrinsic apoptosis in p53-mutated MDA-MB-468 cells. On the contrary, although MnNG induces significant cell death in p53-null Hct116 cells, GSH addition fails to negate MnNG-induced cell death. Thus p53 status with intracellular GSH is critical for the modulation of MnNG-induced apoptosis. Electronic supplementary material The online version of this article (

Purpose: Tumor suppressor genes participate in a variety of critical and highly conserved cell functions, including regulation of the cell cycle and apoptosis, differentiation, surveillance of genomic integrity and repair of DNA errors, signal transduction, and cell adhesion. Genome instability appears to be one of the earliest recognizable phenotypes which appear in carcinogenesis. Studies have shown that the inactivation or deletion of certain tumor suppressor genes contribute to tumor development. Targeted strategies aim to recognize altered proteins and their associated pathways which revealed tremendous therapeutic potential for the cancer treatment. Restoring normal expression of the missing tumor suppressor gene in cancer cells is one of the emerging targeted therapeutic strategies to inhibit tumor development. The genetic determinants for most breast cancer cases remain elusive.
Methods: Targeted strategies aim to recognize altered proteins and their associated pathways which revealed tremendous therapeutic potential for the cancer treatment. Restoring normal expression of the missing tumor suppressor gene in cancer cells is one of the emerging targeted therapeutic strategies to inhibit tumor development.
Results: The genetic determinants for most breast cancer cases remain elusive. However, a mutation in tumor suppressor genes has been determined to be one mechanism of breast carcinogenesis.
Conclusions: This review focuses the therapeutic potential of tumor suppressor genes in breast cancer inhibition.

Caenorhabditis elegans CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that cep-1 inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as isp-1 and nuo-6, but rescued the shortened lifespan of other ETC mutants, such as mev-1 and gas-1. We compared the CEP-1-regulated transcriptional profiles of the long-lived isp-1 and the short-lived mev-1 mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity. Further analyses identified a small subset of CEP-1-regulated genes that displayed distinct expression changes between the isp-1 and mev-1 mutants. Interestingly, this small group of differentially regulated genes are enriched for the ''aging'' Gene Ontology term, consistent with the hypothesis that they might be particularly important for mediating the distinct longevity effects of CEP-1 in isp-1 and mev-1 mutants. We further focused on one of these differentially regulated genes, ftn-1, which encodes ferritin in C. elegans, and demonstrated that it specifically contributed to the extended lifespan of isp-1 mutant worms but did not affect the mev-1 mutant lifespan. We propose that CEP-1 responds to different mitochondrial ETC stress by mounting distinct compensatory responses accordingly to modulate animal physiology and longevity. Our findings provide insights into how mammalian p53 might respond to distinct mitochondrial stressors to influence cellular and organismal responses.