Transcriptional Repression of the Anti-apoptoticsurvivin Gene by Wild Type p53

Hoffman, William H.; Biade, S.; Zilfou, Jack T.; Chen, Jiandong; Murphy, Maureen E.

doi:10.1074/jbc.m106643200

Cited by 710 publications

(661 citation statements)

References 50 publications

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“…46,47 Similarly, we also found that CDDP treatment reduced survivin expression in cells in which it did not activate Akt, including A549 NSCLC, and ZL5 and ZL34 MPM cells (Fig. 3d and data not shown).…”

Section: Discussionsupporting

confidence: 58%

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Belyanskaya¹,

Hopkins-Donaldson²,

Kurtz³

et al. 2005

Intl Journal of Cancer

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The inhibitor of apoptosis protein (IAP) survivin is overexpressed in many tumors but is absent in most normal adult tissues. We report high levels of survivin expression in small cell lung cancer (SCLC), and describe the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in survivin upregulation. Moreover, the cytoprotective function of survivin in response to the anti-cancer agent cisplatin (CDDP) was investigated. Negative modulation of PI3K/ Akt using pharmacological inhibitors or dominant negative Akt (DN-Akt) decreased Akt kinase activity and resulted in decreased survivin expression and phosphorylation on Thr34, whereas transfection of constitutively active Akt (CA-Akt) increased survivin expression and phosphorylation. Interestingly, we found that treatment of SCLC cells with CDDP further increased survivin expression in a cell cycle independent manner by activation of Akt. CA-Akt or lentiviral survivin also inhibited apoptosis induced by CDDP, whereas DN-Akt or survivin-specific RNA interference sensitized cells to CDDP. We identified survivin as an anti-apoptotic protein in SCLC cells that is regulated by Akt, and demonstrate that treatment with the DNA damaging agent CDDP activates the PI3K/Akt/survivin pathway that in part protects cells from drug-induced apoptosis. ' 2005 Wiley-Liss, Inc.

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Section: Discussionsupporting

confidence: 58%

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Belyanskaya¹,

Hopkins-Donaldson²,

Kurtz³

et al. 2005

Intl Journal of Cancer

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“…31 Human survivin is negatively regulated by wild-type p53. 35,50,51 After DNA damage caused by chemotherapy, expression of wild-type p53 is upregulated, expression of survivin is downregulated, and cell-cycle arrest and apoptosis occur. Cells that express mutant p53 do not show these effects after chemotherapeutic treatment.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53

et al. 2004

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Survivin, a member of the inhibitors-of-apoptosis gene family, is overexpressed in many tumor types. Survivin is a prognostic marker of soft-tissue sarcomas, but the downregulation of survivin expression and the possible dependency of survivin downregulation on p53 in these tumors have not been investigated. Therefore, we applied small interfering RNA (siRNA) to knock down the expression of survivin in five human sarcoma cell lines with wild-type or mutant p53 alleles. Compared with survivin mRNA expression in the nonsense siRNA-treated sarcoma cell lines, expression after treatment with survivin-specific siRNA was reduced by 73-88%; survivin protein expression was reduced by 52-81%. This finding was coupled with a reduction in clonogenic survival ranging from 65-86%. However, less than 10% of cells treated with survivin-specific siRNA underwent apoptosis. Cell-cycle and morphologic analyses showed that after a dramatic increase in the number of treated cells in the G2/M phase, some of the cells became polyploid; this result indicates that mitosis of a substantial number of treated cells was incomplete. Our findings suggest that survivin-specific siRNA could be a selective treatment to kill sarcoma cells regardless of the presence or absence of wild-type p53 alleles.

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“…Dozens of genes, including those identified by our group, that are induced by p53 have been isolated and well characterized so far. In addition, many genes that are negatively regulated by p53 such as Survivin, CDC2 and CDC25C have been reported (Taylor et al, 2001;Hoffman et al, 2002). However, the biological significance of genes repressed by p53 is still largely undisclosed.…”

Section: Introductionmentioning

confidence: 99%

CDC20, a potential cancer therapeutic target, is negatively regulated by p53

et al. 2007

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The p53 protein inhibits malignant transformation through direct and indirect regulation of transcription of many genes related to cell cycle, apoptosis and cellular senescence. A number of genes induced by p53 have been well characterized, but biological significance of genes whose expression was suppressed by p53 is still largely undisclosed. To clarify the roles of p53-suppressive genes in carcinogenesis, we analysed two data sets of wholegenome expression profiles, one for cells in which wildtype p53 was exogenously introduced and the other for a large number of clinical cancer tissues. Here, we identified CDC20 that was frequently upregulated in many types of malignancies and remarkably suppressed by ectopic introduction of p53. CDC20 expression was suppressed by genotoxic stresses in p53-and p21-dependent manners through CDE-CHR elements in the CDC20 promoter. Furthermore, small interference RNA (siRNA)-mediated silencing of p53 induced CDC20 expression in normal human dermal fibroblast cells. As we expected, treatment of cancer cells with siRNA against CDC20 induced G 2 /M arrest and suppressed cell growth. Our results indicate that p53 inhibits tumor cell growth through the indirect regulation of CDC20 and that CDC20 might be a good potential therapeutic target for a broad spectrum of human cancer.

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Transcriptional Repression of the Anti-apoptoticsurvivin Gene by Wild Type p53

Cited by 710 publications

References 50 publications

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Knockdown of survivin expression by small interfering RNA reduces the clonogenic survival of human sarcoma cell lines independently of p53

CDC20, a potential cancer therapeutic target, is negatively regulated by p53

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