p53 mediates Bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway

Thomas, Alexander S.; Giesler, Theresa L.; White, Eileen

doi:10.1038/sj.onc.1203895

Cited by 101 publications

(58 citation statements)

References 67 publications

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“…28,29 Studies have directly correlated p53 expression with inhibition of Rac, Cdc42, and Rho mediated cell motility in both epithelial and fibroblastic cells, and loss of p53 expression in tumors and cancer cell lines with increased invasiveness and cell motility. 27,[30][31][32][33][34][35] Therefore, CYFIP2 induction by p53 may directly impinge upon Rac, Cdc42, and Rho activity or alternatively could predominately regulate Rac activity and impact Cdc42 and Rho activity via crosstalk signaling between these Rho family GTPases. 36 Regardless, CYFIP2 is poised as a regulatory scaffolding protein of protein complexes important for actin cytoskeleton regulation and therefore may be the long sought missing link that at least in part mediates p53-dependent regulation of cell motility.…”

Section: Discussionmentioning

confidence: 99%

CYFIP2, a Direct p53 Target, is Leptomycin-B Sensitive

Jackson¹,

Cho²,

Stein³

et al. 2007

Cell Cycle

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Section: Discussionmentioning

confidence: 99%

CYFIP2, a Direct p53 Target, is Leptomycin-B Sensitive

Jackson¹,

Cho²,

Stein³

et al. 2007

Cell Cycle

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“…70 Also, it has been shown that Cdc42/PAK1 can activate JNK1-induced phosphorylation of Bcl-2. 71 Since a phosphorylation-resistant mutant Bcl-2 (S70, 87A, T56, 74A) gains the ability to inhibit Cdc42-mediated apoptosis, this phosphorylation was inactivating. 71 Unexpectedly, this study suggests the involvement of p53 in Bcl-2 phosphorylation, even though in all other studies Bcl-2 phosphorylation occurs regardless of the p53 status.…”

Section: What Kinase Phosphorylates Bcl-2 In Mitotic Arrest?mentioning

confidence: 99%

“…71 Since a phosphorylation-resistant mutant Bcl-2 (S70, 87A, T56, 74A) gains the ability to inhibit Cdc42-mediated apoptosis, this phosphorylation was inactivating. 71 Unexpectedly, this study suggests the involvement of p53 in Bcl-2 phosphorylation, even though in all other studies Bcl-2 phosphorylation occurs regardless of the p53 status. Furthermore, DNA damaging agents, which induce p53, do not lead to Bcl-2 phosphorylation.…”

Section: What Kinase Phosphorylates Bcl-2 In Mitotic Arrest?mentioning

confidence: 99%

Unwinding the loop of Bcl-2 phosphorylation

2001

Leukemia

126

132

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Recent evidence indicates that anti-apoptotic functions of Bcl-2 can be regulated by its phosphorylation. According to the 'mitotic arrest-induced' model, multi-site phosphorylation of the Bcl-2 loop domain is followed by cell death. In contrast, in cytokine-dependent cell lines, cytokines mediate phosphorylation of Bcl-2 on S70, preventing apoptosis. As discussed in this review, these models are not mutually exclusive but reflect different cellular contexts. During mitotic arrest, signal transduction is unique and is fundamentally different from classical mitogenic signaling, since the nucleus membrane is dissolved, gene expression is reduced, and numerous kinases and regulatory proteins are hyperphosphorylated. Hyperphosphorylation of Bcl-2 mediated by paclitaxel and other microtubuleactive drugs is strictly dependent on targeting microtubules that in turn cause mitotic arrest. In addition to serine-70 (S70), microtubule-active agents promote phosphorylation of S87 and threonine-69 (T69), inactivating Bcl-2. A major obstacle for identification of the mitotic Bcl-2 kinase(s) is that inhibition of putative kinase(s) by any means (dominant-negative mutants, antisense oligonucleotides, pharmacological agents) may arrest cycle, preventing mitosis and Bcl-2 phosphorylation. The role of Bcl-2 phosphorylation in cell death is discussed. Leukemia (2001) 15, 869-874.

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“…(b) BL41-3 cells were incubated in the absence or presence of taxol (0.1 mM) for 11.5 h, with cells being exposed to 32 Porthophosphoric acid during the final 3 h; CHO cells that had been transiently transfected with WT-MCL1 were incubated with 32 Porthophosphoric acid for 2.5 h, and either exposed or not exposed to okadaic acid (1 mM) for 1.5 h. The MCL1 protein was immunoprecipitated and subjected to 2D-phosphopeptide mapping using thermolysin. Arrows indicate novel phosphopeptides exhibiting similar migration patterns with okadaic acid and taxol, while the asterisk indicates a distinctive phosphopeptide on stress-activated protein kinases, which are of interest because these are among the various candidate MCL1/ BCL2 kinases (Blagosklonny et al, 1997;Maundrell et al, 1997;Scatena et al, 1998;Srivastava et al, 1998;Basu et al, 2000;Fan et al, 2000;Furukawa et al, 2000;Thomas et al, 2000;Deng et al, 2001;Inoshita et al, 2002; but see also Du et al, 2004). For example, exogenous overexpression of ASK-1 plus either JNK or p38 can stimulate MCL1 phosphorylation in transfected HEK293 cells (Inoshita et al, 2002).…”

mentioning

confidence: 99%

MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol

et al. 2004

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BCL2 family members are subject to regulation at multiple levels, providing checks on their ability to contribute to tumorigenesis. However, findings on posttranslational BCL2 phosphorylation in different systems have been difficult to integrate. Another antiapoptotic family member, MCL1, exhibits a difference in electrophoretic mobility upon phosphorylation induced by an activator of PKC (12-O-tetradecanoylphorbol 13-acetate; TPA) versus agents that act on microtubules or protein phosphatases 1/2A. A multiple pathway model is now presented, which demonstrates that MCL1 can undergo distinct phosphorylation events -mediated through separate signaling processes and involving different target sites -in cells that remain viable in the presence of TPA versus cells destined to die upon exposure to taxol or okadaic acid. Specifically, TPA induces phosphorylation at a conserved extracellular signal-regulated kinase (ERK) site in the PEST region (Thr 163) and slows turnover of the normally rapidly degraded MCL1 protein; however, okadaic acid and taxol induce ERK-independent MCL1 phosphorylation at additional discrete sites. These findings add a new dimension to our understanding of the complex regulation of antiapoptotic BCL2 family members by demonstrating that, in addition to transcriptional and post-transcriptional regulation, MCL1 is subject to multiple, separate, post-translational phosphorylation events, produced in living versus dying cells at ERKinducible versus ERK-independent sites.

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p53 mediates Bcl-2 phosphorylation and apoptosis via activation of the Cdc42/JNK1 pathway

Cited by 101 publications

References 67 publications

CYFIP2, a Direct p53 Target, is Leptomycin-B Sensitive

CYFIP2, a Direct p53 Target, is Leptomycin-B Sensitive

Unwinding the loop of Bcl-2 phosphorylation

MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol

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