A novel site of AKT‐mediated phosphorylation in the human MDM2 onco‐protein

Milne, Diane; Kampanis, Petros; Nicol, Samantha M.; Dias, Sylvia; Campbell, David G.; Fuller-Pace, Frances V.; Meek, David W.

doi:10.1016/j.febslet.2004.09.081

Cited by 39 publications

(49 citation statements)

References 21 publications

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“…We found that increasing AF concentrations increase Mdm2 ubiquitylation and degradation by the proteasome (Figures 2 and 3), which is consistent with a recent study (Stommel and Wahl, 2004). We also found that under these conditions, there is a reduction of Akt-mediated Mdm2 phosphorylation at serine 166 (Figure 4a), phosphorylation that stabilizes Mdm2 (Feng et al, 2004;Milne et al, 2004). Accordingly, Akt activity (measured as phosphorylation at serine 473) tended to be attenuated with increasing AF concentrations (Figure 4a).…”

Section: Discussionsupporting

confidence: 80%

Dose–response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686288)

Meng

Pommier

2007

Oncogene

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Aminoflavone (AF, NSC 686288) is beginning clinical trials. It induces replication-mediated histone H2AX phosphorylation, DNA-protein crosslinks and activates p53. Here, we studied p21 CIP1/WAF1 and Mdm2 responses to AF. Although p53 stabilization and phosphorylation at serine 15 increased with dose and time of exposure, Mdm2 and p21 CIP1/WAF1 protein levels displayed a biphasic response, as they accumulated at submicromolar doses and then decreased with increasing AF. As both Mdm2 and p21 CIP1/WAF1 mRNA levels increased with AF concentration without reduction at higher concentrations, we measured the half-lives of Mdm2 and p21proteins. Mdm2 and p21 CIP1/WAF1 half-lives were shortened with increasing AF concentrations. Proteasomal degradation appears responsible for the decrease of both Mdm2 and p21 CIP1/WAF1, as MG-132 prevented their degradation and revealed AF-induced Mdm2 polyubiquitylation. AF also induced protein kinase B (Akt) activation, which was reduced with increasing AF concentrations. Suppression of Akt by small interfering RNA was associated with downregulation of Mdm2 and p21 CIP1/WAF1 and with enhanced apoptosis. These results suggest that the cellular responses to AF are determined at least in part by Mdm2 and p21 CIP1/WAF1 protein levels, as well as by Akt activity, leading either to cell cycle arrest when Mdm2 and p21 CIP1/WAF1 are elevated, or to apoptosis when Mdm2 and p21 CIP1/WAF1 are degraded by the proteasome and Akt insufficiently activated to protect against apoptosis.

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Section: Discussionsupporting

confidence: 80%

Dose–response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686288)

Meng

Pommier

2007

Oncogene

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“…Although p53 facilitates FLIP downregulation (Fukazawa et al, 2001) and p53 level and function could be correlated with FLIP downregulation in response to various cellular stimuli (Fukazawa et al, 2001;Chandrasekaran et al, 2006), this report provides the first direct evidence for a role of p53 in FLIP degradation. Indeed, Akt has been shown to upregulate FLIP content (Panka et al, 2001;Suhara et al, 2001;Nam et al, 2002Nam et al, , 2003Skurk et al, 2004;Alladina et al, 2005;Sta¨rck et al, 2005;Moriyama and Yonehara 2007;Moumen et al, 2007;Shim et al, 2007) and/or to alter p53 content by activating MDM2 (Mayo and Donner 2001;Zhou et al, 2001;Milne et al, 2004). Our results provide strong evidence that Akt may have a wide-ranging anti-apoptotic role, which includes interfering with the FLIP-p53 binding and FLIP ubiquitination.…”

Section: Discussionsupporting

confidence: 55%

Akt promotes chemoresistance in human ovarian cancer cells by modulating cisplatin-induced, p53-dependent ubiquitination of FLICE-like inhibitory protein

et al. 2009

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Although Akt is a determinant of cisplatin (cis-diaminedichloroplatinum (CDDP)) resistance in ovarian cancer cells, which is related in part to its inhibitory action on p53 activation, precisely how Akt confers CDDP resistance is unclear. In this study, we show that CDDP induced p53-dependent Fas-associated death domain-like interleukin-1b-converting enzyme (FLICE)-like inhibitory protein (FLIP) degradation in chemosensitive ovarian cancer cells but not their resistant counterparts. CDDP induced FLIP-p53-Itch interaction, colocalization and FLIP ubiquitination in chemosensitive but not chemoresistant ovarian cancer cells. Moreover, although activated Akt inhibited CDDP-induced FLIP degradation and apoptosis in sensitive cells, these responses were facilitated by dominant-negative Akt expression in chemoresistant cells. Inhibition of Akt function also facilitated p53-FLIP interaction and FLIP ubiquitination, which were attenuated by p53 silencing. These results suggest that Akt confers resistance, in part, by modulating CDDP-induced, p53-dependent FLIP ubiquitination. Understanding the precise etiology of chemoresistance may improve treatment for ovarian cancer.

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“…Although the precise molecular mechanism responsible for the TWIST-induced Akt activation is not clear, recently, a possible link between TWIST and Akt pathway has been suggested. For example, Akt has been shown to interferer with p53/MDM2 pathway, 27,28 which is also a target of TWIST. 7 In addition, it was reported that inactivation of STAT3 in a breast cancer cell line, 4T1, led to downregulation of Akt-phosphorylation which was associated with completely abolished TWIST protein expression.…”

Section: Discussionmentioning

confidence: 99%

Anti‐apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells

Zhang

Wang

Ling

et al. 2007

Intl Journal of Cancer

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TWIST, a basic helix-loop-helix transcription factor, has been reported to be associated with development and progression of human cancer. Recently, over expression of TWIST is found in cancer patients with shorter survival and poor response to chemotherapy. Previously, we found that upregulation of TWIST was responsible for the development of acquired resistance to taxol in a nasopharyngeal carcinoma (NPC) cell line, HNE1-T3 (Wang et al., Oncogene, 2004;24:274). In this study, we investigated the underlying molecular mechanisms responsible for the TWIST-mediated taxol resistance. By comparison of the parental HNE1 and its derivative HNE1-T3 cell lines, we found that the resistance to taxol in HNE1-T3 cells was associated with suppression of taxol-induced apoptosis evidenced by decreased expression of Bak and Bax and increased Bcl-2, as well as inhibition of PARP and caspase cleavage and DNA ladder formation. However, there was no correlation between taxol sensitivity and alterations on G2/M cell cycle distribution, suggesting that the TWIST-induced taxol resistance is mediated through protection against apoptosis but not mitotic arrest. Analysis of additional 8 NPC cell lines showed that upregulation of TWIST was associated with resistance to microtubule disrupting agents, especially taxol, and inactivation of TWIST through small RNA interference led to increased sensitivity to taxol-induced cell death. Subsequent studies also demonstrated that the TWIST-mediated taxol resistance may be regulated through its positive involvement with the Akt pathway. Our findings suggest an underlying molecular mechanism responsible for the TWIST-mediated chemodrug resistance and suggest a target for overcoming taxol resistance in cancer cells. ' 2007 Wiley-Liss, Inc.

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A novel site of AKT‐mediated phosphorylation in the human MDM2 onco‐protein

Cited by 39 publications

References 21 publications

Dose–response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686288)

Dose–response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21WAF1/CIP1 in response to the novel anticancer agent, aminoflavone (NSC 686288)

Akt promotes chemoresistance in human ovarian cancer cells by modulating cisplatin-induced, p53-dependent ubiquitination of FLICE-like inhibitory protein

Anti‐apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells

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