Induction of p21WAF1/CIP1 by human synovial sarcoma-associated chimeric oncoprotein SYT-SSX1

Tsuda, Masumi; Watanabe, Takuya; Seki, Tatsuya; Kimura, Taichi; Sawa, Hirofumi; Minami, Akio; Akagi, Tsuyoshi; Isobe, Ken‐ichi; Nagashima, Kazuo; Tanaka, Shinya

doi:10.1038/sj.onc.1208942

Cited by 21 publications

(23 citation statements)

References 28 publications

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“…In light of our results showing that SS18-SSX1 can promote the ubiquitination of p53, it would be tempting to speculate that this ubiquitination may also alter the p53 response promoting the activation of a subset of p53 target genes. Additionally, Tsuda et al (44) showed that SS18-SSX1 could activate the p21 promoter under basal conditions and in a p53-independent manner. Interestingly, we have previously shown that SS18-SSX1 can induce the transcription of the DNA repair protein XRCC4 (45).…”

Section: Discussionmentioning

confidence: 99%

The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability

D’Arcy

Maruwge

Ryan³

et al. 2008

Molecular Cancer Research

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Mutations of the p53 gene are uncommon in synovial sarcoma, a high-grade tumor genetically characterized by the chromosomal translocation t:(X;18), which results in the fusion of SS18 with members of SSX gene family. Although implicated in tumorigenesis, the mechanisms by which SS18-SSX promotes tumor growth and cell survival are poorly defined. Here, we show that SS18-SSX1 negatively regulates the stability of the tumor suppressor p53 under basal conditions. Overexpression of SS18-SSX1 enhanced p53 ubiquitination and degradation in a manner dependent on the ubiquitin ligase activity of HDM2. The negative effect of SS18-SSX1 expression on p53 was mediated by its ability to promote HDM2 stabilization through inhibition of HDM2 autoubiquitination. Furthermore, SS18-SSX1 expression altered the induction of p53-regulated genes in response to cellular stress by abrogating the transactivation of HDM2, PUMA, and NOXA but not p21. Our data uncover a novel mechanism whereby SS18-SSX1 can negatively regulate p53 tumor-suppressive function by increasing the stability of its negative regulator HDM2 and suggest that chemical compounds that target the p53-HDM2 regulatory axis may be of therapeutic benefit for the treatment of synovial sarcoma.

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Section: Discussionmentioning

confidence: 99%

The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability

D’Arcy

Maruwge

Ryan³

et al. 2008

Molecular Cancer Research

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“…Currently OIS is known to be induced by various kinds of oncogenic stimulation [4]. Subsequently, cell cycle arrest by p16 has been shown to be one of the important mechanisms for OIS, regulated by combination of Ets and Id1 [5].…”

Section: Introductionmentioning

confidence: 99%

A population of BJ fibroblasts escaped from Ras-induced senescence susceptible to transformation

Kohsaka

Sasai

Takahashi

et al. 2011

Biochemical and Biophysical Research Communications

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Oncogenic stimuli such as H-Ras induce oncogene-induced senescence (OIS) in fibroblasts to protect against transformation. Here we found that a population of the human diploid fibroblasts can escape from OIS induced by H-RasV12. We designated these OIS-escaped cells as OISEC (OIS-escaped cells). OISEC lost the expression of p16 which plays an important role for cell cycle arrest for induction of senescence, but OISEC preserved the p16 expression machinery and exhibited senescence by the treatment with hydrogen peroxide (H 2 O 2 ) as stress-induced premature senescence (SIPS). OISEC did not possess anchorage-independent growth potential, and functional disruption of p53 and Rb by SV40 early region encoding large T and small t antigens, induced the aneuploidy phenotype and colony-forming potential of OISEC together with the exhibition of in vivo tumor formation.Finally, we also found that the distinctive feature of OISEC is expression of transcription factors, Oct3/4, SOX2, and Nanog which is closely related to stem-like cell features. This study highlights the presence of a cell population which escaped from OIS, and this OISEC may transform into malignant cancer cells by the additional hits of several genes in vivo.3

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“…This allows repair of possible DNA damages before the next replication cycle. In cells containing only a mutated form of p53, alternative induction pathways of the p21 activity occurs, and its expression can be positively regulated through several p53-independent mechanisms (Gartel and Tyner, 1999;Tsuda et al, 2005;Fang et al, 2007). One of these induction mechanisms of p21 seems to be mediated by S100A11 (Sakaguchi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Rad54B Targeting to DNA Double-Strand Break Repair Sites Requires Complex Formation with S100A11

Murzik

Hemmerich

Weidtkamp‐Peters

et al. 2008

MBoC

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S100A11 is involved in a variety of intracellular activities such as growth regulation and differentiation. To gain more insight into the physiological role of endogenously expressed S100A11, we used a proteomic approach to detect and identify interacting proteins in vivo. Hereby, we were able to detect a specific interaction between S100A11 and Rad54B, which could be confirmed under in vivo conditions. Rad54B, a DNA-dependent ATPase, is described to be involved in recombinational repair of DNA damage, including DNA double-strand breaks (DSBs). Treatment with bleomycin, which induces DSBs, revealed an increase in the degree of colocalization between S100A11 and Rad54B. Furthermore, S100A11/ Rad54B foci are spatially associated with sites of DNA DSB repair. Furthermore, while the expression of p21 WAF1/CIP1 was increased in parallel with DNA damage, its protein level was drastically down-regulated in damaged cells after S100A11 knockdown. Down-regulation of S100A11 by RNA interference also abolished Rad54B targeting to DSBs. Additionally, S100A11 down-regulated HaCaT cells showed a restricted proliferation capacity and an increase of the apoptotic cell fraction. These observations suggest that S100A11 targets Rad54B to sites of DNA DSB repair sites and identify a novel function for S100A11 in p21-based regulation of cell cycle. INTRODUCTIONProteins may exist in several complexes in a spatial and temporal manner to accomplish distinct functions. Analyses of the interacting partners will provide a strong insight into the physiological role of a particular factor. Therefore, it is essential to identify ideally all interacting partners of proteins in vivo to precisely be able to define their biological function. The investigation of protein complexes of solely endogenously expressed proteins avoid the tendency to detect false positive protein-protein interactions of examinations performed in vitro. A multitude of proteins are involved in both the detection and the repair of DNA damages. It is conceivable that some protein complexes involved in these processes are not yet discovered. A severe form of DNA damage that threaten the integrity of the genome are DNA double-strand breaks (DSBs). DSBs can lead to cell cycle arrest or illegitimate DNA rearrangements that can contribute to cell dysfunction, cell death, or carcinogenesis (Hoeijmakers, 2001). Homologous recombination is a major DNA repair pathway by which DSBs are repaired (Lettier et al., 2006).For the identification of specific interacting proteins of S100A11 (S100C, calgizzarin) we used in the present study a proteomic approach comprising mass spectrometry and immunological techniques. S100A11 belongs to the group of S100 proteins that are considered as multitasking proteins involved in several biological processes such as the Ca 2ϩ signaling network, cell growth and motility, cell cycle progression, transcription, and cell differentiation (Schafer and Heizmann, 1996;Donato, 2001;Eckert et al., 2004). It has been proposed that the S100 proteins are involved in...

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Induction of p21WAF1/CIP1 by human synovial sarcoma-associated chimeric oncoprotein SYT-SSX1

Cited by 21 publications

References 28 publications

The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability

The Oncoprotein SS18-SSX1 Promotes p53 Ubiquitination and Degradation by Enhancing HDM2 Stability

A population of BJ fibroblasts escaped from Ras-induced senescence susceptible to transformation

Rad54B Targeting to DNA Double-Strand Break Repair Sites Requires Complex Formation with S100A11

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