Sox-4 is a positive regulator of Hep3B and HepG2 cells' apoptosis induced by prostaglandin (PG)A2 and Δ12-PGJ2

Ahn, Sang‐Gun; Kim, Ho‐Shik; Jeong, Seong-Whan; Kim, Bo-Eun; Rhim, Hyangshuk; Shim, Jae-Yong; Kim, Jin-Woo; Lee, Jeong-Hwa; Kim, In-Kyung

doi:10.1038/emm.2002.34

Cited by 48 publications

(31 citation statements)

References 16 publications

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“…Recently, increasing evidence has shown that SOX4 is highly up-regulated in a number of tumors, including breast cancer (22), lung cancer (24), colon cancer (25), meduloblastoma (26), salivary gland cancer (27), and hepatocellular carcinoma (28). Furthermore, higher SOX4 expression correlates with better survival in bladder tumor patients (29), and it promotes prostaglandina-induced apoptosis in hepatocellular carcinoma (30), suggesting that SOX4 has a potential tumorsuppressive function. However, the precise mechanism by which SOX4 is involved in tumorigenesis remains largely unknown.…”

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confidence: 99%

Induction of SOX4 by DNA damage is critical for p53 stabilization and function

Pan

Zhao²,

Zhang³

et al. 2009

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

124

113

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DNA damage response (DDR) acts as a tumorigenesis barrier, and any defects in the DDR machinery may lead to cancer. SOX4 expression is elevated in many types of tumors; however, its role in DDR is still largely unknown. Here, we show that SOX4, a new DNA damage sensor, is required for the activation of p53 tumor suppressor in response to DNA damage. Notably, SOX4 interacts with and stabilizes p53 protein by blocking Mdm2-mediated p53 ubiquitination and degradation. Furthermore, SOX4 enhances p53 acetylation by interacting with p300/CBP and facilitating p300/CBP/p53 complex formation. In concert with these results, SOX4 promotes cell cycle arrest and apoptosis, and it inhibits tumorigenesis in a p53-dependent manner. Therefore, these findings highlight SOX4 as a potential key factor in regulating DDR-associated cancer.Mdm2 ͉ ubiquitination ͉ tumorigenesis D NA damage response (DDR), a highly conserved response to genotoxic stresses, is the guardian of genomic integrity (1, 2). It has been shown that DDR serves as a barrier to constrain tumor progression in its early stages by inducing cell cycle arrest, DNA repair, or apoptosis (3). A number of components are involved in cellular DDR machinery, in which ATM-Chk2-p53 and ATRChk1-p53 cascade are the key signaling pathways involved (2). A central component of DDR, p53, is one of the most important tumor suppressor proteins (4-8). The major consequence of p53 activation upon DNA damage is the induction of specific target genes, such as p21 WAF , Bax, and Puma, to initiate cell cycle arrest, apoptosis, and DNA repair (4). Cells lacking functional p53 exhibit a partial deficiency in DNA damage repair, resulting in uncontrolled cell proliferation and malignancy. Indeed, p53 gene is either lost or mutated in more than half of all human cancers (9). Around p53 there is a highly regulated network consisting of numerous proteins that interact with p53 and regulate its activity by protein stabilization, posttranscriptional modifications, protein-protein interaction, and protein subcellular localization (10), among which stabilization of p53 is presumed to play a major role in its activation. Under normal conditions, amount and activity of p53 are maintained at low levels by Mdm2, a ubiquitin E3 ligase, which binds to the N terminus of p53 and targets its C-terminal lysine residues for ubiquitination and degradation (11,12). However, in response to DNA damage, p53 protein is rapidly stabilized and activated mostly through multiple posttranslational modifications, such as phosphorylation and acetylation of specific residues in the N-terminal and C-terminal domains. DNA damage-induced p53 phosphorylation, which is mediated by ATM kinase (13, 14), contributes to p53 stability (15). Acetylation of p53 C-terminal lysine residues in p53 stabilizes the protein by preventing Mdm2-mediated ubiquitination of the same residues (16,17). In addition, the activity of p53 is also modulated by its recruitment of transcriptional coactivators or corepressors.SOX4 is a member of the SOX (SRY-re...

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confidence: 99%

Induction of SOX4 by DNA damage is critical for p53 stabilization and function

Pan

Zhao²,

Zhang³

et al. 2009

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

124

113

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“…12 -PGJ2 especially induces Sox-4 protein and this phenom enon is restricted only to 12 -PGJ2, but not to cisplatin (data not shown). Sox-4 was shown to be overexpressed in HepG2 and Hep3B cells by 12 -PGJ2 and induced apoptosis through activation of caspase 1 (Ahn et al, 2002). Also GRR (Gly rich region) region of Sox-4 was proved to induce apoptosis directly for itself (Eun-Hae Hur, unpublished).…”

Section: Discussionmentioning

confidence: 99%

“…To study the mechanism of 12 -PGJ2-induced apoptosis in Hela Cells, we examined caspase-independent pathway together with bcl-2 effects on caspase cascade. 12 -PGJ2 can exert its ability in many ways; through activation of caspase-1 (Ahn et al, 2002) or induce apoptosis regulators, like Sox-4, which directly plays a role in apoptosis (Hur et al, 2004). In the case of 15-deoxy--12,14-PGJ2(15d-PGJ2), the hydrolysis product of 12 -PGJ2, CHOP gene was transcriptionally activated to induce apoptosis (Shoichi et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…12 -PGJ2 is an enzymatic dehydration product of PDJ2 (Fukushima et al, 1982;Fukushima et al, 1994) and 12 -PGJ2 was able to induce apoptosis in HeLa cells via caspase activation . PGs are also reported to regulate expression of variable genes, including Sox-4 (Ahn et al, 2002), Ssf-1 (Ahn et al, 1999), c-myc and hsp70 (Ahn et al, 1998), and these genes seem to positively or negatively regulate the cell death in many tumour cells. 12 -PGJ2-induced Sox-4 is one of the Sox (SRY-HMG box containing) proteins which are assumed to be involved in the regulation of developmental stages in several tissues.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Sox-4 in the cytochrome c-dependent AIF-independent apoptotic pathway in HeLa cells induced by Δ12-prostaglandin J2

Kim

Lee²,

Kim³

et al. 2004

Exp Mol Med

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Abbreviations:12 -PGJ2, 12 -prostaglandin J2; AIF, apoptosisinducing factor; Sox-4, SRY-HMG box protein-4; z-VAD-fmk, Benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethyl ketone A bstract12 -P rostagland in (P G ) J2 is kn o w n to elicit an anti-n eo plastic effects via ap optosis in duction. P revious study show ed 12 -P G J 2 -induced apopto sis u tilized casp ase cascad e th ro u g h cyto chrom e c-depend en t pathw ays in H eLa cells. In this study, the cellular m echanism of 12

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“…The expression of genes and their products, including p53, c-myc, heat shock protein 70, Sox-4 (Sry-HMG box gene) and SSF-1 (a novel splicing factor), are up-and down-regulated by presence of 12 -PGJ2 in human hepatocarcinoma cells. And these genes and their products serve as a positive or negative regulator in 12 -PGJ2-induced apoptotic pathway in tumor cells (Lee et al, 1995;Ahn et al, 1998;Ahn et al, 1999;Ahn et al, 2002). But the precise mechanism by which 12 -PGJ2-initiates the cellular events resulting in cell death is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome C-dependent Fas-independent apoptotic pathway in HeLa cells induced by Δ12-prostaglandin J2

Kim

Roh²,

Kim³

et al. 2003

Exp Mol Med

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Sox-4 is a positive regulator of Hep3B and HepG2 cells' apoptosis induced by prostaglandin (PG)A2 and Δ12-PGJ2

Abstract: We reported earlier that expression of Sox-4 was found to be elevated during prostaglandin (

Cited by 48 publications

References 16 publications

Induction of SOX4 by DNA damage is critical for p53 stabilization and function

Induction of SOX4 by DNA damage is critical for p53 stabilization and function

Involvement of Sox-4 in the cytochrome c-dependent AIF-independent apoptotic pathway in HeLa cells induced by Δ12-prostaglandin J2

Cytochrome C-dependent Fas-independent apoptotic pathway in HeLa cells induced by Δ12-prostaglandin J2

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