Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-fluorouracil (5-FU) is a widely used chemotherapeutic drug for the treatment of a variety of solid tumors. The anti-tumor activity of 5-FU has been attributed in part to its ability to induce p53-dependent cell growth arrest and apoptosis. However, the molecular mechanisms underlying p53 activation by 5-FU remain largely obscure. Here we report that 5-FU treatment leads to p53 stabilization and activation by blocking MDM2 feedback inhibition through ribosomal proteins. 5-FU treatment increased the fraction of ribosome-free L5, L11, and L23 ribosomal proteins and their interaction with MDM2, leading to p53 activation and G1/S arrest. Conversely, individual knockdown of these ribosomal proteins by small interfering RNA prevented the 5-FU-induced p53 activation and reversed the 5-FU-induced G1/S arrest. These results demonstrate that 5-FU treatment triggers a ribosomal stress response so that ribosomal proteins L5, L11, and L23 are released from ribosome to activate p53 by ablating the MDM2-p53 feedback circuit.
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PMID:5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction. 1724 1

Approximately 50% of protein and RNA synthesis in proliferating cells are devoted to ribosomal biogenesis. Coordination between ribosome biogenesis, growth, and proliferation is critical for maintenance of homeostasis and tumor suppression. Aberrant rRNA expression and processing is sensed by p53. Ribosomal stress increases the binding between MDM2 and ribosomal proteins L5, L11, and L23, resulting in p53 stabilization. Our recent study showed that p53 activation by ribosomal stress also involves degradation of MDMX in an MDM2-dependent fashion. Failure to eliminate MDMX due to overexpression results in the sequestration of p53 into inactive complexes, severely impairing p53-dependent cell cycle arrest during ribosomal stress. Furthermore, MDMX overexpression promotes resistance to the chemotherapeutic agent 5-FU, which at low concentrations activates p53 by inhibiting RNA metabolism. Therefore, MDMX is an important regulator of p53 response to ribosomal stress. MDMX overexpression in tumors may significantly influence response to chemotherapy agents that target rRNA biogenesis.
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PMID:Distinct roles of MDMX in the regulation of p53 response to ribosomal stress. 1732 2

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.
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PMID:Putting a finger on growth surveillance: insight into MDM2 zinc finger-ribosomal protein interactions. 1732 73

To understand the cellular functions of HDM2, we attempted to identify novel HDM2-interacting proteins by proteomic analysis. Along with previously identified interactions with the ribosomal proteins, our analysis reveals interactions of HDM2 with the ribosomal translation elongation factor EF1alpha, 40S ribosomal protein S20, tubulins, glyceraldehyde 3-phosphate dehydrogenase, and a proteolysis-inducing factor dermicidin in the absence of tumor suppressor p53. Because a CTCL tumor antigen HD-CL-08 has high degree of homology with EF1alpha, we confirmed interaction of HDM2 with EF1alpha by immunoprecipitation and Western blot analysis in transformed as well as near normal diploid cells. Endogenous HDM2- EF1alpha complex was detected in cancer cells overexpressing HDM2, suggesting a possible role of this interaction in HDM2-mediated oncogenesis. Consistent with their interaction, colocalization of HDM2 and EF1alpha can be detected in the cytoplasm of normal or transformed cells. Amino acid residues 1-58 and 221-325 of HDM2 were found to be essential for its interaction with EF1alpha, suggesting that the interaction is independent of its other ribosomal interacting proteins L5, L11, and L23. Overexpression of HDM2 did not affect translation. Because EF1alpha has been implicated in DNA replication and severing of microtubules, interaction of HDM2 with EF1alpha may signify a p53-independent cell growth regulatory role of HDM2.
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PMID:HDM2-binding partners: interaction with translation elongation factor EF1alpha. 1737 42

Several ribosomal proteins including L11 have been shown to activate p53 by inhibiting oncoprotein MDM2, leading to inhibition of cell cycle progression. Our recent study showed that L11 also inhibits oncoprotein c-Myc. Overexpression of L11 inhibits c-Myc-induced transcription and cell proliferation, while reduction of endogenous L11 increases these c-Myc activities. Interestingly, L11 is a transcriptional target of c-Myc, thus forming a negative feedback loop. We further showed that L11 competes with coactivator TRRAP for binding to c-Myc through the Myc box II (MB II) and reduces histone H4 acetylation at c-Myc target gene promoters. In addition, L11 appears to regulate c-Myc levels. Knocking down L11 markedly increases the mRNA and protein levels of endogenous c-Myc. These results suggest that L11 also inhibits cell cycle progression by regulating the c-Myc pathway. Here we further discuss the implications of this regulation and questions that this finding raises.
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PMID:Feedback regulation of c-Myc by ribosomal protein L11. 1803 16

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used as an immunosuppressive agent. MPA selectively inhibits inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme for the de novo synthesis of guanine nucleotides, leading to depletion of the guanine nucleotide pool. Its chemotherapeutic effects have been attributed to its ability to induce cell cycle arrest and apoptosis. MPA treatment has also been shown to induce and activate p53. However, the mechanism underlying the p53 activation pathway is still unclear. Here, we show that MPA treatment results in inhibition of pre-rRNA synthesis and disruption of the nucleolus. This treatment enhances the interaction of MDM2 with L5 and L11. Interestingly, knockdown of endogenous L5 or L11 markedly impairs the induction of p53 and G(1) cell cycle arrest induced by MPA. These results suggest that MPA may trigger a nucleolar stress that induces p53 activation via inhibition of MDM2 by ribosomal proteins L5 and L11.
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PMID:Mycophenolic acid activation of p53 requires ribosomal proteins L5 and L11. 1830 14

The nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis. Both depletion and overexpression of NS reduce cell proliferation. However, the mechanisms underlying this regulation are still unclear. Here, we show that NS regulates p53 activity through the inhibition of MDM2. NS binds to the central acidic domain of MDM2 and inhibits MDM2-mediated p53 ubiquitylation and degradation. Consequently, ectopic overexpression of NS activates p53, induces G(1) cell cycle arrest, and inhibits cell proliferation. Interestingly, the knockdown of NS by small interfering RNA also activates p53 and induces G(1) arrest. These effects require the ribosomal proteins L5 and L11, since the depletion of NS enhanced their interactions with MDM2 and the knockdown of L5 or L11 abrogated the NS depletion-induced p53 activation and cell cycle arrest. These results suggest that a p53-dependent cell cycle checkpoint monitors changes of cellular NS levels via the impediment of MDM2 function.
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PMID:Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2. 1842 7

MDM2 is a ubiquitin ligase that plays a key role in regulating the stability of the p53 tumor suppressor protein. Several proteins have been shown to activate the p53 pathway by interacting with and inhibiting the E3 function of MDM2, thereby leading to an accumulation of p53. These include the alternate reading frame (ARF) proteins and the ribosomal proteins L5 and L11. We found that when overexpressed alone, L11 is much less potent in inhibiting MDM2 than p14(ARF). However, L11 cooperates with L5, resulting in a robust inhibition of the E3 activity of MDM2, and a stabilization and activation of p53 approaching that achieved by p14(ARF). We further showed that the ability of L11 to bind the 5S rRNA is important for the cooperation with L5, and a mutant L11, which cannot bind the 5S rRNA, cannot cooperate with L5 in inhibiting MDM2.
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PMID:Cooperation between the ribosomal proteins L5 and L11 in the p53 pathway. 1856 Mar 57

Nucleostemin (NS) is a protein concentrated in the nucleolus of most stem cells and also in many tumor cells, which has been implicated in cell-cycle progression owing to its ability to modulate p53. Depletion of NS causes G(1) cell-cycle arrest, but its overexpression does so as well. Recently, this paradox has been clarified. NS overexpression causes a sequestration of murine double minute 2 (MDM2), preventing the destruction of p53. A recent study has demonstrated that loss of NS promotes the interaction of L5 and L11 ribosomal proteins with MDM2 and, thus, also prevents p53 degradation. This new finding expands our understanding of the multiple modes of NS action and reinforces the concept that the nucleolus has key roles in cell-cycle progression.
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PMID:Nucleostemin: a multiplex regulator of cell-cycle progression. 1895 97

Ribosome is responsible for protein synthesis in all organisms and ribosomal proteins (RPs) play important roles in the formation of a functional ribosome. L11 was recently shown to regulate p53 activity through a direct binding with MDM2 and abrogating the MDM2-induced p53 degradation in response to ribosomal stress. However, the studies were performed in cell lines and the significance of this tumor suppressor function of L11 has yet to be explored in animal models. To investigate the effects of the deletion of L11 and its physiological relevance to p53 activity, we knocked down the rpl11 gene in zebrafish and analyzed the p53 response. Contrary to the cell line-based results, our data indicate that an L11 deficiency in a model organism activates the p53 pathway. The L11-deficient embryos (morphants) displayed developmental abnormalities primarily in the brain, leading to embryonic lethality within 6-7 days post fertilization. Extensive apoptosis was observed in the head region of the morphants, thus correlating the morphological defects with apparent cell death. A decrease in total abundance of genes involved in neural patterning of the brain was observed in the morphants, suggesting a reduction in neural progenitor cells. Upregulation of the genes involved in the p53 pathway were observed in the morphants. Simultaneous knockdown of the p53 gene rescued the developmental defects and apoptosis in the morphants. These results suggest that ribosomal dysfunction due to the loss of L11 activates a p53-dependent checkpoint response to prevent improper embryonic development.
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PMID:Loss of ribosomal protein L11 affects zebrafish embryonic development through a p53-dependent apoptotic response. 1912 14


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