The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53

Higashitsuji, Hiroaki; Itoh, Katsuhiko; Sakurai, Toshiharu; Nagao, Toshikazu; Sumitomo, Haruhiko; Masuda, Tomoko; Dawson, Simon; Shimada, Yutaka; Mayer, R. John; Fujita, Jun

doi:10.1016/j.ccr.2005.06.006

Cited by 208 publications

(175 citation statements)

References 48 publications

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“…Analysis of p53 Stability and Ubiquitylation in Vivo-For in vivo p53 degradation assays, U-2 OS cells stably expressing HSCO-FLAG or FLAG alone (three clones each) and H1299 cells co-transfected with plasmids expressing p53 alone or in combination with HSCO-FLAG were used and analyzed as described (24). To analyze the effects of HSCO down-regulation, U-2 OS cells transfected with HSCO-specific short hairpin RNA (shRNA) were used.…”

Section: Methodsmentioning

confidence: 99%

Enhanced Deacetylation of p53 by the Anti-apoptotic Protein HSCO in Association with Histone Deacetylase 1

Higashitsuji

Masuda

Liu

et al. 2007

Journal of Biological Chemistry

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HSCO (hepatoma subtracted-cDNA library clone one, also called ETHE1) was originally identified by its frequent overexpression in hepatocellular carcinomas. HSCO inhibits function of NF-B by binding to RelA and accelerating its export from the nucleus. We show here that HSCO exhibits anti-apoptotic activity in cells exposed to DNA-damaging agents by suppressing transcriptional activity of p53. Induction of pro-apoptotic genes, Noxa, Perp, PIG3, and Bax were suppressed in cells overexpressing HSCO. By increasing ubiquitylation and degradation of p53, HSCO reduces p53 protein levels. HSCO specifically associates with histone deacetylase 1 (HDAC1) independently of Mdm2 and facilitates deacetylation of p53 at Lys-373/382 by HDAC1. The metallo-␤-lactamase family consensus sequence in HSCO is important for its effect on p53 deacetylation. Coimmunoprecipitation and immunofluorescence studies suggested that HSCO, HDAC1, and p53 form a complex in the nucleus. Thus, HSCO is a cofactor that increases the deacetylase activity of HDAC1 toward p53, leading to suppression of apoptosis. Treatment of hepatocellular carcinomas that retain wildtype p53 and overexpress HSCO with anti-HSCO agents might re-establish the p53 response and revert chemoresistance.

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Section: Methodsmentioning

confidence: 99%

Enhanced Deacetylation of p53 by the Anti-apoptotic Protein HSCO in Association with Histone Deacetylase 1

Higashitsuji

Masuda

Liu

et al. 2007

Journal of Biological Chemistry

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“…Recently, increasing amounts of data suggest that p53 ubiquitination and degradation are more complex than once thought. More E3 ligases were found with specificity for p53 dependent or independent of Hdm2 (22)(23)(24). In this paper, we demonstrate that PACT is another negative regulator of p53 by the involvement of Hdm2, acting as an E3 ligase.…”

Section: Discussionmentioning

confidence: 63%

PACT is a negative regulator of p53 and essential for cell growth and embryonic development

Deng²,

Xing³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The tumor suppressor p53 regulates cell cycle progression and apoptosis in response to various types of stress, whereas excess p53 activity creates unwanted effects. Tight regulation of p53 is essential for maintaining normal cell growth. p53-associated cellular protein-testes derived (PACT, also known as P2P-R, RBBP6) is a 250-kDa Ring finger-containing protein that can directly bind to p53. PACT is highly up-regulated in esophageal cancer and may be a promising target for immunotherapy. However, the physiological role of the PACT-p53 interaction remains largely unclear. Here, we demonstrate that the disruption of PACT in mice leads to early embryonic lethality before embryonic day 7.5 (E7.5), accompanied by an accumulation of p53 and widespread apoptosis. p53-null mutation partially rescues the lethality phenotype and prolonged survival to E11.5. Endogenous PACT can interact with Hdm2 and enhance Hdm2-mediated ubiquitination and degradation of p53 as a result of the increase of the p53-Hdm2 affinity. Consequently, PACT represses p53-dependent gene transcription. Knockdown of PACT significantly attenuates the p53-Hdm2 interaction, reduces p53 polyubiquitination, and enhances p53 accumulation, leading to both apoptosis and cell growth retardation. Taken together, our data demonstrate that the PACT-p53 interaction plays a critical role in embryonic development and tumorigenesis and identify PACT as a member of negative regulators of p53.apoptosis ͉ embryonic lethality ͉ ubiquitination

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“…5). Knockdown of RAP80 had little effect on the basal level of p53 protein, unlike YY1 and gankyrin, modifiers of the p53-HDM2 loop that inhibit basal p53 activity (32,33). It is interesting that RAP80 knockdown resulted in reduced Ser(P) 15 -p53 phosphorylation after IR ( Fig.…”

Section: Discussionmentioning

confidence: 93%

“…RAP80 itself does not have an intrinsic ubiquitin E3 ligase activity because it lacks a Ring or a HECT domain. Instead of strengthening the p53-HDM2 interaction, as described for YY1 and gankyrin (32,33), RAP80 enhanced HDM2 ligase activity, as indicated by increased HDM2 ubiquitination, the mechanism of which remains to be determined. Unlike RAP80 regulation of ER␣ and BRCA1 signaling (11,12,16), the UIMs of RAP80 are not required for p53-regulation.…”

Section: Discussionmentioning

confidence: 98%

“…6. It is well known that the p53-HDM2 auto-regulatory loop controls p53 level during DDR and is subject to fine-tuning through a number of proteins that include ARF (31), YY1 (32), gankyrin (33), nucleophosmin (34), WIP1 (35), and NUMB (36). These proteins regulate p53-HDM2 interaction and/or HDM2 localization, stability, and ligase activity, which in turn stimulate or prevent HDM2-mediated ubiquitination and p53 degradation.…”

Section: Discussionmentioning

confidence: 99%

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A Regulatory Loop Composed of RAP80-HDM2-p53 Provides RAP80-enhanced p53 Degradation by HDM2 in Response to DNA Damage

Yan¹,

Menéndez

Xiao³

et al. 2009

Journal of Biological Chemistry

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The ubiquitin interaction motif-containing protein RAP80 plays a key role in DNA damage response signaling. Using genomic and functional analysis, we established that the expression of the RAP80 gene is regulated in a DNA damage-responsive manner by the master regulator p53. This regulation occurs at the transcriptional level through a noncanonical p53 response element in the RAP80 promoter. Although it is inducible by p53, RAP80 is also able to regulate p53 through an association with both p53 and the E3 ubiquitin ligase HDM2, providing HDM2-dependent enhancement of p53 polyubiquitination. Depletion of RAP80 by small interfering RNA stabilizes p53, which, following DNA damage, results in an increased transactivation of several p53 target genes as well as greater apoptosis. Consistent with these observations, exogenous expression of RAP80 selectively inhibits p53-dependent transactivation of target genes in an mdm2-dependent manner in MEF cells. Thus, we identify a new DNA damage-associated role for RAP80. It can function in an autoregulatory loop consisting of RAP80, HDM2, and the p53 master regulatory network, implying an important role for this loop in genome stability and oncogenesis.

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The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53

Cited by 208 publications

References 48 publications

Enhanced Deacetylation of p53 by the Anti-apoptotic Protein HSCO in Association with Histone Deacetylase 1

Enhanced Deacetylation of p53 by the Anti-apoptotic Protein HSCO in Association with Histone Deacetylase 1

PACT is a negative regulator of p53 and essential for cell growth and embryonic development

A Regulatory Loop Composed of RAP80-HDM2-p53 Provides RAP80-enhanced p53 Degradation by HDM2 in Response to DNA Damage

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