The Experts below are selected from a list of 13182 Experts worldwide ranked by ideXlab platform
Yanping Zhang - One of the best experts on this subject based on the ideXlab platform.
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Nutrient availability dictates the regulation of metabolism by the ribosomal Protein-MDM2-p53 pathway
Molecular & cellular oncology, 2018Co-Authors: Derek A. Franklin, Yanping ZhangAbstract:Nutrient availability alters ribosomal biogenesis, causing ribosomal Proteins to act as secondary messengers of nutrient response by binding to MDM2 and activating p53. Recent work suggests that the ribosomal Protein (RP)-MDM2-p53 pathway responds to the deficiency or overabundance of nutrients through seemingly contradictory mechanisms; however, both of these responses promote organism survival.
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The Evolution of the Ribosomal Protein-MDM2-p53 Pathway.
Cold Spring Harbor perspectives in medicine, 2016Co-Authors: Chad Deisenroth, Derek A. Franklin, Yanping ZhangAbstract:The progression of our understanding of ribosomal Proteins as static building blocks of the ribosome to highly integrated sensors of p53 surveillance and function has achieved a tremendous rate of growth over the past several decades. As the workhorse of the cell, ribosomes are responsible for translating the genetic code into the functional units that drive cell growth and proliferation. The seminal identification of ribosomal Protein binding to MDM2, the negative regulator of p53, has evolved into a paradigm for ribosomal Protein-MDM2-p53 signaling that extends into processes as diverse as energy metabolism to proliferation. The central core of signaling occurs when perturbations to rRNA synthesis, processing, and assembly modulate the rate of ribosome biogenesis, signaling a nucleolar stress response to p53. This has led to identification of a number of disease pathologies related to ribosomal Protein dysfunction that are manifested as developmental disorders or cancer. Advancing research into the basic mechanics of ribosomal Protein-MDM2-p53 signaling is paving the way for novel translational research into biomarker identification and therapeutic strategies for ribosome-related diseases.
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The Ribosomal Protein-MDM2-p53 Pathway and Energy Metabolism: Bridging the Gap between Feast and Famine.
Genes & cancer, 2011Co-Authors: Chad Deisenroth, Yanping ZhangAbstract:Cellular growth and division are two fundamental processes that are exquisitely sensitive and responsive to environmental fluctuations. One of the most energetically demanding functions of these processes is ribosome biogenesis, the key component to regulating overall Protein synthesis and cell growth. Perturbations to ribosome biogenesis have been demonstrated to induce an acute stress response leading to p53 activation through the inhibition of MDM2 by a number of ribosomal Proteins. The energy status of a cell is a highly dynamic variable that naturally contributes to metabolic fluctuations, which can affect both the rates of ribosome biogenesis and p53 function. This, in turn, determines whether a cell is in an anabolic, growth-promoting state or a catabolic, growth-suppressing state. Here the authors integrate the known functions of p53 to postulate how changes in nutrient availability may induce the ribosomal Protein–MDM2-p53 signaling pathway to modulate p53-dependent metabolic regulation.
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an arf independent c myc activated tumor suppression pathway mediated by ribosomal Protein MDM2 interaction
Cancer Cell, 2010Co-Authors: Everardo Macias, Chad Deisenroth, Mikael S. Lindström, Aiwen Jin, Krishna P Bhat, Hua Mao, Yanping ZhangAbstract:In vitro studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal Protein (RP)-mediated suppression of MDM2 E3 ligase activity. To study the physiological significance of the RP-MDM2 interaction, we generated mice carrying a cancer-associated cysteine-to-phenylalanine substitution in the zinc finger of MDM2 that disrupted its binding to RPL5 and RPL11. Mice harboring this mutation, retain normal p53 response to DNA damage, but lack of p53 response to perturbations in ribosome biogenesis. Loss of RP-MDM2 interaction significantly accelerates Eμ-Myc-induced lymphomagenesis. Furthermore, ribosomal perturbation-induced p53 response does not require tumor suppressor p19ARF. Collectively, our findings establish RP-MDM2 interaction as a genuine p53 stress-signaling pathway activated by aberrant ribosome biogenesis and essential for safeguarding against oncogenic c-MYC-induced tumorigenesis.
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Signaling to p53: ribosomal Proteins find their way.
Cancer cell, 2009Co-Authors: Yanping ZhangAbstract:Inherently disparate cell growth and division, which are intimately coupled through a delicate network of intracellular and extracellular signaling, require ribosomal biogenesis. A number of events imparting instability to ribosomal biogenesis can cause nucleolar stress. In response to this stress, several ribosomal Proteins bind to MDM2 and block MDM2-mediated p53 ubiquitination and degradation, resulting in p53-dependent cell cycle arrest. By doing so, the ribosomal Proteins play a crucial role in connecting deregulated cell growth with inhibition of cell division. The ribosomal Protein-MDM2-p53 signaling pathway provides a molecular switch that may constitute a surveillance network monitoring the integrity of ribosomal biogenesis.
Pierre Hainaut - 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, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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, ΔN-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, ΔN-p53 oligomerizes with full-length p53 (FL-p53) and negatively regulates its transcriptional and growth-suppressive activities. Consistent with the lack of MDM2 binding, ΔN-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, ΔN-p53 becomes the predominant p53 form during the synchronous progression into S phase after serum stimulation. These results suggest that ΔN-p53 may play a role as a transient, negative regulator of p53 during cell cycle progression.
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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, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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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Delta N-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53
Oncogene, 2002Co-Authors: Stéphanie Courtois, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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.
Chad Deisenroth - One of the best experts on this subject based on the ideXlab platform.
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The Evolution of the Ribosomal Protein-MDM2-p53 Pathway.
Cold Spring Harbor perspectives in medicine, 2016Co-Authors: Chad Deisenroth, Derek A. Franklin, Yanping ZhangAbstract:The progression of our understanding of ribosomal Proteins as static building blocks of the ribosome to highly integrated sensors of p53 surveillance and function has achieved a tremendous rate of growth over the past several decades. As the workhorse of the cell, ribosomes are responsible for translating the genetic code into the functional units that drive cell growth and proliferation. The seminal identification of ribosomal Protein binding to MDM2, the negative regulator of p53, has evolved into a paradigm for ribosomal Protein-MDM2-p53 signaling that extends into processes as diverse as energy metabolism to proliferation. The central core of signaling occurs when perturbations to rRNA synthesis, processing, and assembly modulate the rate of ribosome biogenesis, signaling a nucleolar stress response to p53. This has led to identification of a number of disease pathologies related to ribosomal Protein dysfunction that are manifested as developmental disorders or cancer. Advancing research into the basic mechanics of ribosomal Protein-MDM2-p53 signaling is paving the way for novel translational research into biomarker identification and therapeutic strategies for ribosome-related diseases.
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The Ribosomal Protein-MDM2-p53 Pathway and Energy Metabolism: Bridging the Gap between Feast and Famine.
Genes & cancer, 2011Co-Authors: Chad Deisenroth, Yanping ZhangAbstract:Cellular growth and division are two fundamental processes that are exquisitely sensitive and responsive to environmental fluctuations. One of the most energetically demanding functions of these processes is ribosome biogenesis, the key component to regulating overall Protein synthesis and cell growth. Perturbations to ribosome biogenesis have been demonstrated to induce an acute stress response leading to p53 activation through the inhibition of MDM2 by a number of ribosomal Proteins. The energy status of a cell is a highly dynamic variable that naturally contributes to metabolic fluctuations, which can affect both the rates of ribosome biogenesis and p53 function. This, in turn, determines whether a cell is in an anabolic, growth-promoting state or a catabolic, growth-suppressing state. Here the authors integrate the known functions of p53 to postulate how changes in nutrient availability may induce the ribosomal Protein–MDM2-p53 signaling pathway to modulate p53-dependent metabolic regulation.
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an arf independent c myc activated tumor suppression pathway mediated by ribosomal Protein MDM2 interaction
Cancer Cell, 2010Co-Authors: Everardo Macias, Chad Deisenroth, Mikael S. Lindström, Aiwen Jin, Krishna P Bhat, Hua Mao, Yanping ZhangAbstract:In vitro studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal Protein (RP)-mediated suppression of MDM2 E3 ligase activity. To study the physiological significance of the RP-MDM2 interaction, we generated mice carrying a cancer-associated cysteine-to-phenylalanine substitution in the zinc finger of MDM2 that disrupted its binding to RPL5 and RPL11. Mice harboring this mutation, retain normal p53 response to DNA damage, but lack of p53 response to perturbations in ribosome biogenesis. Loss of RP-MDM2 interaction significantly accelerates Eμ-Myc-induced lymphomagenesis. Furthermore, ribosomal perturbation-induced p53 response does not require tumor suppressor p19ARF. Collectively, our findings establish RP-MDM2 interaction as a genuine p53 stress-signaling pathway activated by aberrant ribosome biogenesis and essential for safeguarding against oncogenic c-MYC-induced tumorigenesis.
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Ribosome biogenesis surveillance: probing the ribosomal Protein-MDM2-p53 pathway
Oncogene, 2010Co-Authors: Chad Deisenroth, Yangjun ZhangAbstract:The dynamic processes of cell growth and cell division remain under constant surveillance. As one of the primary ‘gatekeepers’ of the cell, p53 has a major role in sensing a variety of stressors to maintain cellular homeostasis. Growth is driven by new Protein synthesis, a process that requires robust manufacture of ribosomes in the nucleolus. Ribosome biogenesis is a complex process comprising transcription, modification, and processing of ribosomal RNA, production of ribosomal Proteins (RPs) and auxiliary factors, and coordinated assembly of ribonucleoProtein particles to produce mature ribosomes. As the major function of the nucleolus, ribosome biogenesis demands a considerable amount of resources and must be maintained in a coordinated manner to ensure fidelity of the process. Perturbations to many aspects of ribosome biogenesis are thought to contribute to ‘nucleolar stress’ and trigger a RP-MDM2-p53 stress response pathway. In this review, we will clarify how disruption to three major components of ribosome biogenesis can trigger nucleolar stress and activate p53, thereby lending support to a RP-MDM2-p53 ribosome biogenesis surveillance pathway.
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Putting a Finger on Growth Surveillance Insight into MDM2 Zinc Finger-Ribosomal Protein Interactions
Cell cycle (Georgetown Tex.), 2007Co-Authors: Mikael S. Lindström, Chad Deisenroth, Yanping ZhangAbstract:A number of events imparting instability to ribosomal biogenesis can cause nucleolar stress and trigger activation of a p53 checkpoint. Following nucleolar stress, ribosomal Proteins L5, L11 and L23 bind to MDM2, blocking MDM2-mediated p53 ubiquitination and degradation. The MDM2 C4 zinc finger domain has been shown to play an important role in this process. Mutations targeting the C4 zinc finger of MDM2 have been reported in human cancers, and now a potential rationale for the occurrence of these mutations in cancer has emerged. Here we further discuss these findings and propose the existence of a ribosomal Protein-MDM2-p53 surveillance network responsible for monitoring the stability of the transition between cell growth and division.
Stéphanie Courtois - 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, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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, ΔN-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, ΔN-p53 oligomerizes with full-length p53 (FL-p53) and negatively regulates its transcriptional and growth-suppressive activities. Consistent with the lack of MDM2 binding, ΔN-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, ΔN-p53 becomes the predominant p53 form during the synchronous progression into S phase after serum stimulation. These results suggest that ΔN-p53 may play a role as a transient, negative regulator of p53 during cell cycle progression.
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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, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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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Delta N-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53
Oncogene, 2002Co-Authors: Stéphanie Courtois, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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.
Sophie North - 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, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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, ΔN-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, ΔN-p53 oligomerizes with full-length p53 (FL-p53) and negatively regulates its transcriptional and growth-suppressive activities. Consistent with the lack of MDM2 binding, ΔN-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, ΔN-p53 becomes the predominant p53 form during the synchronous progression into S phase after serum stimulation. These results suggest that ΔN-p53 may play a role as a transient, negative regulator of p53 during cell cycle progression.
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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, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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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Delta N-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53
Oncogene, 2002Co-Authors: Stéphanie Courtois, Gerald Verhaegh, Sophie North, Maria-gloria Luciani, Ula Hibner, Patrice Lassus, Moshe Oren, 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.
