Modulation of p53 and MDM2 activity by novel interaction with Ras-GAP binding proteins (G3BP)

Kim, MM; Wiederschain, Dmitri; Kennedy, Derek; Hansen, Erica; Zhang, Yuan

doi:10.1038/sj.onc.1210212

Cited by 77 publications

(68 citation statements)

References 19 publications

(24 reference statements)

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“…Overexpression of G3BP1 was reported to increase S-phase entry in fibroblasts, and the overexpression was associated with the intact RNAbinding domain (10). Additionally, after binding with p53, G3BP1 expression led to the redistribution of p53 from the nucleus to the cytoplasm (11). The overall evidence suggests that specifically overexpressed G3BP1 in a range of cancers might be a candidate target for anticancer agents.…”

Section: Introductionmentioning

confidence: 82%

Epigallocatechin Gallate Suppresses Lung Cancer Cell Growth through Ras–GTPase-Activating Protein SH3 Domain-Binding Protein 1

Shim

Chae

et al. 2010

Cancer Prevention Research

105

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Green tea is a highly popular beverage globally. Green tea contains a number of polyphenol compounds referred to as catechins, and (−)-epigallocatechin gallate (EGCG) is believed to be the major biologically active compound found in green tea. EGCG has been reported to suppress lung cancer, but the molecular mechanisms of the inhibitory effects of EGCG are not clear. We found that EGCG interacted with the Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) with high binding affinity (K d = 0.4 μmol/L). We also showed that EGCG suppressed anchorage-independent growth of H1299 and CL13 lung cancer cells, which contain an abundance of the G3BP1 protein. EGCG was much less effective in suppressing anchorage-independent growth of H460 lung cancer cells, which express much lower levels of G3BP1. Knockdown shG3BP1-transfected H1299 cells exhibited substantially decreased proliferation and anchorage-independent growth. shG3BP1 H1299 cells were resistant to the inhibitory effects of EGCG on growth and colony formation compared with shMock-transfected H1299 cells. EGCG interfered with the interaction of G3BP1 and the Ras-GTPase-activating protein and further suppressed the activation of Ras. Additional results revealed that EGCG effectively attenuated G3BP1 downstream signaling, including extracellular signal-regulated kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, in wild-type H1299 and shMock H1299 cells but had little effect on H460 or shG3BP1 H1299 cells. Overall, these results strongly indicate that EGCG suppresses lung tumorigenesis through its binding with G3BP1. Cancer Prev Res; 3(5); 670-9. ©2010 AACR.

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Section: Introductionmentioning

confidence: 82%

Epigallocatechin Gallate Suppresses Lung Cancer Cell Growth through Ras–GTPase-Activating Protein SH3 Domain-Binding Protein 1

Shim

Chae

et al. 2010

Cancer Prevention Research

105

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“…G3BP interacts with RAS GTPase-activating protein p120, a protein involved in the mammalian RAS signaling pathway. G3BP is essential for mouse development, and its expression is increased in many human cancer cell types (Barnes et al 2002;Kim et al 2007). Interestingly, G3BP is reported to have multiple activities related to cellular RNA metabolism, including RNA helicase activity, phosphorylation-dependent endoribonuclease activity, and cytoplasmic stress granule facilitator activity (Atlas et al 2007;Solomon et al 2007;Ortega et al 2010).…”

Section: Resultsmentioning

confidence: 99%

The essential polysome-associated RNA-binding protein RBP42 targets mRNAs involved in Trypanosoma brucei energy metabolism

Das

Morales

Banday

et al. 2012

RNA

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RNA-binding proteins that target mRNA coding regions are emerging as regulators of post-transcriptional processes in eukaryotes. Here we describe a newly identified RNA-binding protein, RBP42, which targets the coding region of mRNAs in the insect form of the African trypanosome, Trypanosoma brucei. RBP42 is an essential protein and associates with polysome-bound mRNAs in the cytoplasm. A global survey of RBP42-bound mRNAs was performed by applying HITS-CLIP technology, which captures protein-RNA interactions in vivo using UV light. Specific RBP42-mRNA interactions, as well as mRNA interactions with a known RNA-binding protein, were purified using specific antibodies. Target RNA sequences were identified and quantified using high-throughput RNA sequencing. Analysis revealed that RBP42 bound mainly within the coding region of mRNAs that encode proteins involved in cellular energy metabolism. Although the mechanism of RBP42's function is unclear at present, we speculate that RBP42 plays a critical role in modulating T. brucei energy metabolism.

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“…Indeed, although MDM2 interacts with proteins, fulfilling a variety of cellular functions (p300, pRb, Numb, MTBP (MDM2-binding protein), DNA polymerase ⑀, promyelocytic leukemia protein, Tip60, YY1, insulin-like growth factor 1 receptor, glucocorticoid receptor/estrogen receptor, androgen receptor, hypoxia-inducible factor 1, p73, NF-B, PSD-95, ADP ribosylation factor, E2F1, TATA-binding protein, TAFII250, Sp1, ribosomal L5, TSG 101, Ras-GAP binding proteins), the biological significance of these multiple interactions remains to be explained (for review, see Refs. 15,22). It should be stressed that not all MDM2 client proteins are targeted for proteasome-dependent degradation; hence, not all involvement of MDM2 protein can be explained by its E3 ubiquitin ligase activity (13,15).…”

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confidence: 99%

MDM2 Chaperones the p53 Tumor Suppressor

Wawrzynów

Żylicz

Wallace

et al. 2007

Journal of Biological Chemistry

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The murine double minute (mdm2) gene encodes an E3 ubiquitin ligase that plays a key role in the degradation of p53 tumor suppressor protein. Nevertheless recent data highlight other p53-independent functions of MDM2. Given that MDM2 protein binds ATP, can interact with the Hsp90 chaperone, plays a role in the modulation of transcription factors and protection and activation of DNA polymerases, and is involved in ribosome assembly and nascent p53 protein biosynthesis, we have evaluated and found MDM2 protein to possess an intrinsic molecular chaperone activity. MDM2 can substitute for the Hsp90 molecular chaperone in promoting binding of p53 to the p21-derived promoter sequence. This reaction is driven by recycling of MDM2 from the p53 complex, triggered by binding of ATP to MDM2. The ATP binding mutant MDM2 protein (K454A) lacks the chaperone activity both in vivo and in vitro. Mdm2 cotransfected in the H1299 cell line with wild-type p53 stimulates efficient p53 folding in vivo but at the same time accelerates the degradation of p53. MDM2 in which one of the Zn 2؉ coordinating residues is mutated (C478S or C464A) blocks degradation but enhances folding of p53. This is the first demonstration that MDM2 possesses an intrinsic molecular chaperone activity, indicating that the ATP binding function of MDM2 can mediate its chaperone function toward the p53 tumor suppressor.The p53 tumor suppressor gene encodes a sequence-specific transcription factor that is mutated in the vast majority of human cancers (1). Two other paralogs of p53, namely p63 and p73, have been identified, but the physiological functions of each member of the p53 family appear to be rather distinct (for review, see Refs. 2 and 3). One of the foremost characterized target genes of p53 is the mdm2 gene. MDM2 protein possesses E3 ubiquitin ligase activity toward p53 that plays a role in the negative regulation of p53 and its degradation by the proteasome (for review, see Ref. 4).Through its ability to ubiquitylate p53 and target it for proteasomal degradation, MDM2 plays a key role in maintaining p53 at very low levels under non-stress conditions. In such circumstances MDM2 and p53 form a negative feedback loop in which p53 induces mdm2 transcription and MDM2 targets p53 for degradation (2). In stress situations, MDM2-dependent degradation of p53 is inhibited by a variety of mechanisms, including p14ARF binding to MDM2, phosphorylation of the C terminus of MDM2 by the ATM kinase, stress-induced phosphorylation of sites in the trans-activation domain of p53, subsequent binding of the p300 coactivator, and further acetylation of p53 in its C-terminal region (5), which results in an increase of the steady-state level of the p53 transcription factor and consequential flux in the expression of more than a hundred genes, including those involved in cell cycle arrest, senescence, and apoptosis (2).Recent reports indicate that apart from its initially discovered RING finger-dependent enzymatic E3 ubiquitin ligase activity, MDM2 has other functions. A hydroph...

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Modulation of p53 and MDM2 activity by novel interaction with Ras-GAP binding proteins (G3BP)

Cited by 77 publications

References 19 publications

Epigallocatechin Gallate Suppresses Lung Cancer Cell Growth through Ras–GTPase-Activating Protein SH3 Domain-Binding Protein 1

Epigallocatechin Gallate Suppresses Lung Cancer Cell Growth through Ras–GTPase-Activating Protein SH3 Domain-Binding Protein 1

The essential polysome-associated RNA-binding protein RBP42 targets mRNAs involved in Trypanosoma brucei energy metabolism

MDM2 Chaperones the p53 Tumor Suppressor

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