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Keerthana Gnanapradeepan - One of the best experts on this subject based on the ideXlab platform.
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the P53 tumor suppressor in the control of metabolism and ferroptosis
Frontiers in Endocrinology, 2018Co-Authors: Keerthana Gnanapradeepan, Subhasree Basu, Thibaut Barnoud, Anna Budinakolomets, Chepei Kung, Maureen E MurphyAbstract:The P53 tumor suppressor continues to be distinguished as the most frequently mutated gene in human cancer. It is widely believed that the ability of P53 to induce senescence and programmed cell death underlies the tumor suppressor functions of P53. However, P53 has a number of other functions that recent data strongly implicate in tumor suppression, particularly with regard to the control of metabolism and ferroptosis (iron- and lipid-peroxide-mediated cell death) by P53. As reviewed here, the roles of P53 in the control of metabolism and ferroptosis are complex. Wild type (WT) P53 negatively regulates lipid synthesis and glycolysis in normal and tumor cells, and positively regulates oxidative phosphorylation and lipid catabolism. Mutant P53 in tumor cells does the converse, positively regulating lipid synthesis and glycolysis. The role of P53 in ferroptosis is even more complex: in normal tissues, WT P53 appears to positively regulate ferroptosis, and this pathway appears to play a role in the ability of basal, unstressed P53 to suppress tumor initiation and development. In tumors, other regulators of ferroptosis supersede P53’s role, and WT P53 appears to play a limited role; instead mutant P53 sensitizes tumor cells to ferroptosis. By clearly elucidating the roles of WT and mutant P53 in metabolism and ferroptosis, and establishing these roles in tumor suppression, emerging research promises to yield new therapeutic avenues for cancer and metabolic diseases.
Clodagh C Oshea - One of the best experts on this subject based on the ideXlab platform.
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heterochromatin silencing of P53 target genes by a small viral protein
Nature, 2010Co-Authors: Conrado Soria, Fanny E Estermann, Kristen C Espantman, Clodagh C OsheaAbstract:The transcription factor P53 (also known as TP53) guards against tumour and virus replication and is inactivated in almost all cancers. P53-activated transcription of target genes is thought to be synonymous with the stabilization of P53 in response to oncogenes and DNA damage. During adenovirus replication, the degradation of P53 by E1B-55k is considered essential for P53 inactivation, and is the basis for P53-selective viral cancer therapies. Here we reveal a dominant epigenetic mechanism that silences P53-activated transcription, irrespective of P53 phosphorylation and stabilization. We show that another adenoviral protein, E4-ORF3, inactivates P53 independently of E1B-55k by forming a nuclear structure that induces de novo H3K9me3 heterochromatin formation at P53 target promoters, preventing P53–DNA binding. This suppressive nuclear web is highly selective in silencing P53 promoters and operates in the backdrop of global transcriptional changes that drive oncogenic replication. These findings are important for understanding how high levels of wild-type P53 might also be inactivated in cancer as well as the mechanisms that induce aberrant epigenetic silencing of tumour-suppressor loci. Our study changes the longstanding definition of how P53 is inactivated in adenovirus infection and provides key insights that could enable the development of true P53-selective oncolytic viral therapies. The P53 transcription factor is both a tumour suppressor, inactivated in almost all cancers, and a defence against adenovirus replication. Adenovirus E1B-55K targets P53 for degradation, and is thought to be crucial for P53 inactivation during adenovirus replication. Indeed, mutant viruses lacking E1B-55K have been tested as viral cancer therapies that are selective for P53-positive tumours. Soria et al. now show that another adenoviral protein, E4-ORF3, can inactivate P53 independently of E1B-55K through a chromatin-silencing mechanism that prevents access of P53 to its DNA. This work suggests that P53 inactivation in adenovirus infection is a more complex process than previously thought, and that it might be possible to develop true P53 selective antitumour viral therapies once this system is more fully understood. Adenovirus E1B-55k targets transcription factor P53 for degradation and is thought to be critical for P53 inactivation during adenovirus replication. Indeed, mutant viruses lacking E1B-55k have been tested as viral cancer therapies selective for P53-positive tumours. These authors find another adenoviral protein, E4-ORF3, to inactivate P53 independently of E1B-55k by means of a chromatin-silencing mechanism that prevents access of P53 to its DNA target sites.
Moshe Oren - One of the best experts on this subject based on the ideXlab platform.
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ΔN-P53, a natural isoform of P53 lacking the first transactivation domain, counteracts growth suppression by wild-type P53
Oncogene, 2002Co-Authors: Stéphanie Courtois, Moshe Oren, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Patrice Lassus, Ula Hibner, Pierre HainautAbstract:The tumor suppressor protein P53 is ubiquitously expressed as a major isoform of 53 kD, but several forms of lower molecular weight have been observed. Here, we describe a new isoform, DeltaN-P53, produced by internal initiation of translation at codon 40 and lacking the N-terminal first transactivation domain. This isoform has impaired transcriptional activation capacity, and does not complex with the P53 regulatory protein Mdm2. Furthermore, DeltaN-P53 oligomerizes with full-length P53 (FL-P53) and negatively regulates its transcriptional and growth-suppressive activities. Consistent with the lack of Mdm2 binding, DeltaN-P53 does not accumulate in response to DNA-damage, suggesting that this isoform is not involved in the response to genotoxic stress. However, in serum-starved cells expressing wild-type P53, DeltaN-P53 becomes the predominant P53 form during the synchronous progression into S phase after serum stimulation. These results suggest that DeltaN-P53 may play a role as a transient, negative regulator of P53 during cell cycle progression.
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CRITICAL ROLE FOR SER20 OF HUMAN P53 IN THE NEGATIVE REGULATION OF P53 BY MDM2
The EMBO Journal, 1999Co-Authors: Tamar Unger, Guillermina Lozano, Moshe Oren, Tamar Juven-gershon, Eli Moallem, Michael Berger, Ronit Vogt Sionov, Ygal HauptAbstract:In response to environmental stress, the P53 phosphoprotein is stabilized and activated to inhibit cell growth. P53 stability and activity are negatively regulated by the murine double minute (Mdm2) oncoprotein in an autoregulatory feedback loop. The inhibitory effect of Mdm2 on P53 has to be tightly regulated for proper P53 activity. Phosphorylation is an important level of P53 regulation. In response to DNA damage, P53 is phosphorylated at several N-terminal serines. In this study we examined the role of Ser20, a potential phosphorylation site in human P53, in the regulation of P53 stability and function. Substitution of Ser20 by Ala (P53-Ala20) significantly increases the susceptibility of human P53 to negative regulation by Mdm2 in vivo, as measured by apoptosis and transcription activation assays. Mutation of Ser20 to Ala renders P53 less stable and more prone to Mdm2-mediated degradation. While the in vitro binding of P53 to Mdm2 is not increased by the Ala20 mutation, the same mutation results in a markedly enhanced binding in vivo. This is consistent with the conclusion that phosphorylation of Ser20 in vivo attenuates the binding of wild-type P53 to Mdm2. Peptides bearing non-phosphorylated Ser20 or Ala20 compete with P53 for Mdm2 binding, while a similar peptide with phosphorylated Ser20 does not. This implies a critical role for Ser20 in modulating the negative regulation of P53 by Mdm2, probably through phosphorylation-dependent inhibition of P53-Mdm2 interaction.
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mdm2 promotes the rapid degradation of P53
Nature, 1997Co-Authors: Ygal Haupt, Ruth Maya, Anat Kazaz, Moshe OrenAbstract:The P53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress1. The activity of P53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins1,2. The Mdm2 oncoprotein is a potent inhibitor of P53 (ref. 3). Mdm2 binds the transcriptional activation domain of P53 and blocks its ability to regulate target genes3,4 and to exert antiproliferative effects4–7. On the other hand, P53 activates the expression of the mdm2 gene1 in an autoregulatory feedback loop3. The interval between P53 activation and consequent Mdm2 accumulation defines a time window during which P53 exerts its effects8. We now report that Mdm2 also promotes the rapid degradation of P53 under conditions in which P53 is otherwise stabilized. This effect of Mdm2 requires binding of P53; moreover, a small domain of P53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant P53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid P53 loss. We propose that the Mdm2-promoted degradation of P53 provides a new mechanism to ensure effective termination of the P53 signal.
Scott W Lowe - One of the best experts on this subject based on the ideXlab platform.
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PML Is a Direct P53 Target that Modulates P53 Effector Functions
Molecular Cell, 2004Co-Authors: Elisa De Stanchina, E Querido, Gerardo Ferbeyre, Masako Narita, Ramana V. Davuluri, Pier Paolo Pandolfi, Scott W LoweAbstract:The P53 tumor suppressor promotes cell cycle arrest or apoptosis in response to stress. Previous work suggests that the promyelocytic leukemia gene (PML) can act upstream of P53 to enhance transcription of P53 targets by recruiting P53 to nuclear bodies (NBs). We show that PML is itself a P53 target gene that also acts downstream of P53 to potentiate its antiproliferative effects. Hence, P53 is required for PML induction in response to oncogenes and DNA damaging chemotherapeutics. Furthermore, the PML gene contains P53 binding sites that confer P53 responsiveness to a heterologous reporter and can bind P53 in vitro and in vivo. Finally, cells lacking PML show a reduced propensity to undergo senescence or apoptosis in response to P53 activation, despite the induction of several P53 target genes. These results identify an additional element of PML regulation and establish PML as a mediator of P53 tumor suppressor functions.
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Oncogenic ras and P53 cooperate to induce cellular senescence
Molecular and Cellular Biology, 2002Co-Authors: Gerardo Ferbeyre, Athena W. Lin, Mila E. Mccurrach, E Querido, Elisa De Stanchina, Gregory J. Hannon, Scott W LoweAbstract:Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/P53 tumor suppressor pathway. To investigate whether P53 is sufficient to induce senescence, we introduced a conditional murine P53 allele (P53(val135)) into P53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing P53, oncogenic Ras, or both gene products. Conditional P53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with P53 enhanced both P53 levels and activity relative to that observed for P53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19(ARF) was required for this effect, since P53(-/-) ARF(-/-) double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and P53. Although the levels of exogenous P53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on P53 could not explain the cooperation between oncogenic Ras and P53 in promoting senescence. Hence, enforced P53 expression without oncogenic ras in P53(-/-) mdm2(-/-) double-null cells produced extremely high P53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts P53 into a senescence inducer through both quantitative and qualitative mechanisms.
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P53 and p73: seeing double?
Nature Genetics, 2000Co-Authors: María S Soengas, Scott W LoweAbstract:Whereas p73 is closely related to the tumour-suppressor protein P53, its contribution to tumour suppression and the spatial and temporal regulation of its isoforms is unclear. It has now been established that p73 is a transcriptional target of E2F1. Its ability to induce apoptosis in TP53 ^ −/− cells indicates a tumour-control mechanism that runs parallel to but independent of that mediated by P53. The new results illustrate a complex cross-talk between P53, E2F1 and p73.
Ygal Haupt - One of the best experts on this subject based on the ideXlab platform.
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CRITICAL ROLE FOR SER20 OF HUMAN P53 IN THE NEGATIVE REGULATION OF P53 BY MDM2
The EMBO Journal, 1999Co-Authors: Tamar Unger, Guillermina Lozano, Moshe Oren, Tamar Juven-gershon, Eli Moallem, Michael Berger, Ronit Vogt Sionov, Ygal HauptAbstract:In response to environmental stress, the P53 phosphoprotein is stabilized and activated to inhibit cell growth. P53 stability and activity are negatively regulated by the murine double minute (Mdm2) oncoprotein in an autoregulatory feedback loop. The inhibitory effect of Mdm2 on P53 has to be tightly regulated for proper P53 activity. Phosphorylation is an important level of P53 regulation. In response to DNA damage, P53 is phosphorylated at several N-terminal serines. In this study we examined the role of Ser20, a potential phosphorylation site in human P53, in the regulation of P53 stability and function. Substitution of Ser20 by Ala (P53-Ala20) significantly increases the susceptibility of human P53 to negative regulation by Mdm2 in vivo, as measured by apoptosis and transcription activation assays. Mutation of Ser20 to Ala renders P53 less stable and more prone to Mdm2-mediated degradation. While the in vitro binding of P53 to Mdm2 is not increased by the Ala20 mutation, the same mutation results in a markedly enhanced binding in vivo. This is consistent with the conclusion that phosphorylation of Ser20 in vivo attenuates the binding of wild-type P53 to Mdm2. Peptides bearing non-phosphorylated Ser20 or Ala20 compete with P53 for Mdm2 binding, while a similar peptide with phosphorylated Ser20 does not. This implies a critical role for Ser20 in modulating the negative regulation of P53 by Mdm2, probably through phosphorylation-dependent inhibition of P53-Mdm2 interaction.
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mdm2 promotes the rapid degradation of P53
Nature, 1997Co-Authors: Ygal Haupt, Ruth Maya, Anat Kazaz, Moshe OrenAbstract:The P53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress1. The activity of P53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins1,2. The Mdm2 oncoprotein is a potent inhibitor of P53 (ref. 3). Mdm2 binds the transcriptional activation domain of P53 and blocks its ability to regulate target genes3,4 and to exert antiproliferative effects4–7. On the other hand, P53 activates the expression of the mdm2 gene1 in an autoregulatory feedback loop3. The interval between P53 activation and consequent Mdm2 accumulation defines a time window during which P53 exerts its effects8. We now report that Mdm2 also promotes the rapid degradation of P53 under conditions in which P53 is otherwise stabilized. This effect of Mdm2 requires binding of P53; moreover, a small domain of P53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant P53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid P53 loss. We propose that the Mdm2-promoted degradation of P53 provides a new mechanism to ensure effective termination of the P53 signal.