This study focuses on the effects of Myc oncoprotein on the translational apparatus of the cell. ... more This study focuses on the effects of Myc oncoprotein on the translational apparatus of the cell. Translation is an energy consuming process that involves a large number of accessory factors. The production of components of the protein synthesis machinery can be regulated at the transcriptional level by specific factors.
PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors an... more PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 Kip1 and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.
Various mitogenic or growth inhibitory stimuli induce a rapid change in the association of termin... more Various mitogenic or growth inhibitory stimuli induce a rapid change in the association of terminal oligopyrimidine (TOP) mRNAs with polysomes. It is generally believed that such translational control hinges on the mammalian target of rapamycin (mTOR)-S6 kinase pathway. Amino acid availability affects the translation of TOP mRNAs, although the signaling pathway involved in this regulation is less well characterized. To investigate both serum-and amino acid-dependent control of TOP mRNA translation and the signaling pathways involved, HeLa cells were subjected to serum and/or amino acid deprivation and stimulation. Our results indicate the following. 1) Serum and amino acid deprivation had additive effects on TOP mRNA translation. 2) The serum content of the medium specifically affected TOP mRNA translation, whereas amino acid availability affected both TOP and non-TOP mRNAs. 3) Serum signaling to TOP mRNAs involved only a rapamycin-sensitive pathway, whereas amino acid signaling depended on both rapamycin-sensitive and rapamycininsensitive but wortmannin-sensitive events. 4) Eukaryotic initiation factor-2␣ phosphorylation increased during amino acid deprivation, but not following serum deprivation. Interestingly, rapamycin treatment suggests a novel connection between the mTOR pathway and eukaryotic initiation factor-2␣ phosphorylation in mammalian cells, which may not, however, be involved in TOP mRNA translational regulation.
This is an open-access article distributed under the terms of the Creative Commons Attribution Li... more This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore... more The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes.
Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's... more Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's disease. The presence of iron together with a-synuclein in Lewy bodies, the increase of iron in the substantia nigra and the correlation between polymorphism of the several genes implicated in iron metabolism and Parkinson's disease, support a role for iron in the neurodegeneration. Analysis of post mortem brains revealed increased amount of insoluble a-synuclein protein despite unchanged/reduced levels of a-synuclein mRNA in Parkinson's disease. Interestingly, on the basis of the presence of a putative iron responsive element in the 5 0-UTR, it has been suggested that there is a possible iron-dependent translational control of human a-synuclein mRNA. Considering the similarity between the sequences present in human a-synuclein mRNA and the ferritin iron responsive element, we postulated that iron deficiency would decrease the translation of a-synuclein mRNA. Here we used HEK293 cells treated with iron chelator deferoxamine or ferric ammonium citrate to verify the possible iron-dependent translational control of human a-synuclein biosynthesis. We show that the amount of polysome-associated endogenous human a-synuclein mRNA decreases in presence of deferoxamine. Our data demonstrate that human a-synuclein expression is regulated by iron mainly at the translational level. This result not only supports a role for iron in the translational control of a-synuclein expression, but also suggests that iron chelation may be a valid approach to control a-synuclein levels in the brain.
Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6... more Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6-12 pyrimidines at the 59 end and by a growth-associated translational regulation. All vertebrate genes for the 80 ribosomal proteins and some other genes involved, directly or indirectly, in translation, are TOP genes. Among the numerous translation factors, only eEF1A and eEF2 are known to be encoded by TOP genes, most of the others having not been analyzed. Here, we report a systematic analysis of the human genes for translation factors. Our results show that: (1) all five elongation factors are encoded by TOP genes; and (2) among the initiation and termination factors analyzed, only eIF3e, eIF3f, and eIF3h exhibit the characteristics of TOP genes. Interestingly, these three polypeptides have been recently shown to constitute a specific subgroup among eIF3 subunits. In fact, eIF3e, eIF3f, and eIF3h are the part of the functional core of eIF3 that is not conserved in Saccharomyces cerevisiae. It has been hypothesized that they are regulatory subunits, and the fact that they are encoded by TOP genes may be relevant for their function.
Figure 1: Cisplatin treatment induces accumulation of TAp63 and death in early postnatal oocytes.... more Figure 1: Cisplatin treatment induces accumulation of TAp63 and death in early postnatal oocytes. Imatinib counteracts the cisplatin-induced effects in vitro. (a) Ovary sections from P5 mice treated for 2 h with or without cisplatin (CDDP, 20 M) stained with an antibody to p63 (red). Scale bar, 25 m. (b) Western blots of p63, phospho-H2AX (phoH2AX) and tubulin in ovary extracts after cisplatin treatment. MW, molecular weight. (c) Western blots stained as in b after cisplatin (20 M) treatment for the indicated lengths of time. (d) Top, magnification of ovary sections showing-H2AX foci after 24 h of cisplatin (20 M); bottom, ovary sections cultured for 36 h with or without cisplatin (20 M) stained with TUNEL (red). Scale bar, 25 m. (e) Quantification of-H2AX foci. Data represent the means s.d. (n = 100). (f) Left, western blots of p63, c-Abl and lamin in ovary extracts treated with cisplatin (20 M) alone or in combination with imatinib (10 M); right, protein quantification. (g) Ovary ...
The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore... more The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes.
Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6... more Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6–12 pyrimidines at the 5′ end and by a growth-associated translational regulation. All vertebrate genes for the 80 ribosomal proteins and some other genes involved, directly or indirectly, in translation, are TOP genes. Among the numerous translation factors, only eEF1A and eEF2 are known to be encoded by TOP genes, most of the others having not been analyzed. Here, we report a systematic analysis of the human genes for translation factors. Our results show that: (1) all five elongation factors are encoded by TOP genes; and (2) among the initiation and termination factors analyzed, only eIF3e, eIF3f, and eIF3h exhibit the characteristics of TOP genes. Interestingly, these three polypeptides have been recently shown to constitute a specific subgroup among eIF3 subunits. In fact, eIF3e, eIF3f, and eIF3h are the part of the functional core of eIF3 that is not conserved in Saccharomyces cere...
PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors an... more PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 Kip1 and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.
Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's... more Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's disease. The presence of iron together with a-synuclein in Lewy bodies, the increase of iron in the substantia nigra and the correlation between polymorphism of the several genes implicated in iron metabolism and Parkinson's disease, support a role for iron in the neurodegeneration. Analysis of post mortem brains revealed increased amount of insoluble a-synuclein protein despite unchanged/reduced levels of a-synuclein mRNA in Parkinson's disease. Interestingly, on the basis of the presence of a putative iron responsive element in the 5 0-UTR, it has been suggested that there is a possible iron-dependent translational control of human a-synuclein mRNA. Considering the similarity between the sequences present in human a-synuclein mRNA and the ferritin iron responsive element, we postulated that iron deficiency would decrease the translation of a-synuclein mRNA. Here we used HEK293 cells treated with iron chelator deferoxamine or ferric ammonium citrate to verify the possible iron-dependent translational control of human a-synuclein biosynthesis. We show that the amount of polysome-associated endogenous human a-synuclein mRNA decreases in presence of deferoxamine. Our data demonstrate that human a-synuclein expression is regulated by iron mainly at the translational level. This result not only supports a role for iron in the translational control of a-synuclein expression, but also suggests that iron chelation may be a valid approach to control a-synuclein levels in the brain.
R. Massa, M. B. Panico, S. Caldarola, F. R. Fusco, P. Sabatelli, C. Terracciano, A. Botta, G. Nov... more R. Massa, M. B. Panico, S. Caldarola, F. R. Fusco, P. Sabatelli, C. Terracciano, A. Botta, G. Novelli, G. Bernardi and F. Loreni (2010) Neuropathology and Applied Neurobiology36, 275–284 The myotonic dystrophy type 2 (DM2) gene product zinc finger protein 9 (ZNF9) is associated with sarcomeres and normally localized in DM2 patients' muscles Aims: Myotonic dystrophy type 2 (DM2) is caused by a [CCTG]n intronic expansion in the zinc finger protein 9 (ZNF9) gene. As for DM1, sharing with DM2 a similar phenotype, the pathogenic mutation involves a transcribed but untranslated genomic region, suggesting that RNA toxicity may have a role in the pathogenesis of these multisystem disorders by interfering with common cellular mechanisms. However, haploinsufficiency has been described in DM1 and DM2 animal models, and might contribute to pathogenesis. The aim of the present work was therefore to assess ZNF9 protein expression in rat tissues and in human muscle, and ZNF9 subcellular distri...
This study focuses on the effects of Myc oncoprotein on the translational apparatus of the cell. ... more This study focuses on the effects of Myc oncoprotein on the translational apparatus of the cell. Translation is an energy consuming process that involves a large number of accessory factors. The production of components of the protein synthesis machinery can be regulated at the transcriptional level by specific factors.
PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors an... more PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 Kip1 and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.
Various mitogenic or growth inhibitory stimuli induce a rapid change in the association of termin... more Various mitogenic or growth inhibitory stimuli induce a rapid change in the association of terminal oligopyrimidine (TOP) mRNAs with polysomes. It is generally believed that such translational control hinges on the mammalian target of rapamycin (mTOR)-S6 kinase pathway. Amino acid availability affects the translation of TOP mRNAs, although the signaling pathway involved in this regulation is less well characterized. To investigate both serum-and amino acid-dependent control of TOP mRNA translation and the signaling pathways involved, HeLa cells were subjected to serum and/or amino acid deprivation and stimulation. Our results indicate the following. 1) Serum and amino acid deprivation had additive effects on TOP mRNA translation. 2) The serum content of the medium specifically affected TOP mRNA translation, whereas amino acid availability affected both TOP and non-TOP mRNAs. 3) Serum signaling to TOP mRNAs involved only a rapamycin-sensitive pathway, whereas amino acid signaling depended on both rapamycin-sensitive and rapamycininsensitive but wortmannin-sensitive events. 4) Eukaryotic initiation factor-2␣ phosphorylation increased during amino acid deprivation, but not following serum deprivation. Interestingly, rapamycin treatment suggests a novel connection between the mTOR pathway and eukaryotic initiation factor-2␣ phosphorylation in mammalian cells, which may not, however, be involved in TOP mRNA translational regulation.
This is an open-access article distributed under the terms of the Creative Commons Attribution Li... more This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore... more The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes.
Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's... more Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's disease. The presence of iron together with a-synuclein in Lewy bodies, the increase of iron in the substantia nigra and the correlation between polymorphism of the several genes implicated in iron metabolism and Parkinson's disease, support a role for iron in the neurodegeneration. Analysis of post mortem brains revealed increased amount of insoluble a-synuclein protein despite unchanged/reduced levels of a-synuclein mRNA in Parkinson's disease. Interestingly, on the basis of the presence of a putative iron responsive element in the 5 0-UTR, it has been suggested that there is a possible iron-dependent translational control of human a-synuclein mRNA. Considering the similarity between the sequences present in human a-synuclein mRNA and the ferritin iron responsive element, we postulated that iron deficiency would decrease the translation of a-synuclein mRNA. Here we used HEK293 cells treated with iron chelator deferoxamine or ferric ammonium citrate to verify the possible iron-dependent translational control of human a-synuclein biosynthesis. We show that the amount of polysome-associated endogenous human a-synuclein mRNA decreases in presence of deferoxamine. Our data demonstrate that human a-synuclein expression is regulated by iron mainly at the translational level. This result not only supports a role for iron in the translational control of a-synuclein expression, but also suggests that iron chelation may be a valid approach to control a-synuclein levels in the brain.
Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6... more Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6-12 pyrimidines at the 59 end and by a growth-associated translational regulation. All vertebrate genes for the 80 ribosomal proteins and some other genes involved, directly or indirectly, in translation, are TOP genes. Among the numerous translation factors, only eEF1A and eEF2 are known to be encoded by TOP genes, most of the others having not been analyzed. Here, we report a systematic analysis of the human genes for translation factors. Our results show that: (1) all five elongation factors are encoded by TOP genes; and (2) among the initiation and termination factors analyzed, only eIF3e, eIF3f, and eIF3h exhibit the characteristics of TOP genes. Interestingly, these three polypeptides have been recently shown to constitute a specific subgroup among eIF3 subunits. In fact, eIF3e, eIF3f, and eIF3h are the part of the functional core of eIF3 that is not conserved in Saccharomyces cerevisiae. It has been hypothesized that they are regulatory subunits, and the fact that they are encoded by TOP genes may be relevant for their function.
Figure 1: Cisplatin treatment induces accumulation of TAp63 and death in early postnatal oocytes.... more Figure 1: Cisplatin treatment induces accumulation of TAp63 and death in early postnatal oocytes. Imatinib counteracts the cisplatin-induced effects in vitro. (a) Ovary sections from P5 mice treated for 2 h with or without cisplatin (CDDP, 20 M) stained with an antibody to p63 (red). Scale bar, 25 m. (b) Western blots of p63, phospho-H2AX (phoH2AX) and tubulin in ovary extracts after cisplatin treatment. MW, molecular weight. (c) Western blots stained as in b after cisplatin (20 M) treatment for the indicated lengths of time. (d) Top, magnification of ovary sections showing-H2AX foci after 24 h of cisplatin (20 M); bottom, ovary sections cultured for 36 h with or without cisplatin (20 M) stained with TUNEL (red). Scale bar, 25 m. (e) Quantification of-H2AX foci. Data represent the means s.d. (n = 100). (f) Left, western blots of p63, c-Abl and lamin in ovary extracts treated with cisplatin (20 M) alone or in combination with imatinib (10 M); right, protein quantification. (g) Ovary ...
The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore... more The synthesis of adequate amounts of ribosomes is an essential task for the cell. It is therefore not surprising that regulatory circuits exist to organize the synthesis of ribosomal components. It has been shown that defect in ribosome biogenesis (ribosomal stress) induces apoptosis or cell cycle arrest through activation of the tumor suppressor p53. This mechanism is thought to be implicated in the pathophysiology of a group of genetic diseases such as Diamond Blackfan Anemia which are called ribosomopathies. We have identified an additional response to ribosomal stress that includes the activation of eukaryotic translation elongation factor 2 kinase with a consequent inhibition of translation elongation. This leads to a translational reprogramming in the cell that involves the structurally defined group of messengers called terminal oligopyrimidine (TOP) mRNAs which encode ribosomal proteins and translation factors. In fact, while general protein synthesis is decreased by the impairment of elongation, TOP mRNAs are recruited on polysomes causing a relative increase in the synthesis of TOP mRNA-encoded proteins compared to other proteins. Therefore, in response to ribosomal stress, there is a change in the translation pattern of the cell which may help restore a sufficient level of ribosomes.
Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6... more Terminal oligopyrimidine (TOP) mRNAs (encoded by the TOP genes) are identified by a sequence of 6–12 pyrimidines at the 5′ end and by a growth-associated translational regulation. All vertebrate genes for the 80 ribosomal proteins and some other genes involved, directly or indirectly, in translation, are TOP genes. Among the numerous translation factors, only eEF1A and eEF2 are known to be encoded by TOP genes, most of the others having not been analyzed. Here, we report a systematic analysis of the human genes for translation factors. Our results show that: (1) all five elongation factors are encoded by TOP genes; and (2) among the initiation and termination factors analyzed, only eIF3e, eIF3f, and eIF3h exhibit the characteristics of TOP genes. Interestingly, these three polypeptides have been recently shown to constitute a specific subgroup among eIF3 subunits. In fact, eIF3e, eIF3f, and eIF3h are the part of the functional core of eIF3 that is not conserved in Saccharomyces cere...
PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors an... more PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 Kip1 and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.
Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's... more Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson's disease. The presence of iron together with a-synuclein in Lewy bodies, the increase of iron in the substantia nigra and the correlation between polymorphism of the several genes implicated in iron metabolism and Parkinson's disease, support a role for iron in the neurodegeneration. Analysis of post mortem brains revealed increased amount of insoluble a-synuclein protein despite unchanged/reduced levels of a-synuclein mRNA in Parkinson's disease. Interestingly, on the basis of the presence of a putative iron responsive element in the 5 0-UTR, it has been suggested that there is a possible iron-dependent translational control of human a-synuclein mRNA. Considering the similarity between the sequences present in human a-synuclein mRNA and the ferritin iron responsive element, we postulated that iron deficiency would decrease the translation of a-synuclein mRNA. Here we used HEK293 cells treated with iron chelator deferoxamine or ferric ammonium citrate to verify the possible iron-dependent translational control of human a-synuclein biosynthesis. We show that the amount of polysome-associated endogenous human a-synuclein mRNA decreases in presence of deferoxamine. Our data demonstrate that human a-synuclein expression is regulated by iron mainly at the translational level. This result not only supports a role for iron in the translational control of a-synuclein expression, but also suggests that iron chelation may be a valid approach to control a-synuclein levels in the brain.
R. Massa, M. B. Panico, S. Caldarola, F. R. Fusco, P. Sabatelli, C. Terracciano, A. Botta, G. Nov... more R. Massa, M. B. Panico, S. Caldarola, F. R. Fusco, P. Sabatelli, C. Terracciano, A. Botta, G. Novelli, G. Bernardi and F. Loreni (2010) Neuropathology and Applied Neurobiology36, 275–284 The myotonic dystrophy type 2 (DM2) gene product zinc finger protein 9 (ZNF9) is associated with sarcomeres and normally localized in DM2 patients' muscles Aims: Myotonic dystrophy type 2 (DM2) is caused by a [CCTG]n intronic expansion in the zinc finger protein 9 (ZNF9) gene. As for DM1, sharing with DM2 a similar phenotype, the pathogenic mutation involves a transcribed but untranslated genomic region, suggesting that RNA toxicity may have a role in the pathogenesis of these multisystem disorders by interfering with common cellular mechanisms. However, haploinsufficiency has been described in DM1 and DM2 animal models, and might contribute to pathogenesis. The aim of the present work was therefore to assess ZNF9 protein expression in rat tissues and in human muscle, and ZNF9 subcellular distri...
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