p21-Activated Kinase 1 Phosphorylates the Death Agonist Bad and Protects Cells from Apoptosis

Schürmann, Annette; Mooney, Aisling; Sanders, Luraynne C.; Sells, Mary Ann; Wang, Hong Gang; Reed, John C.; Bokoch, Gary M.

doi:10.1128/mcb.20.2.453-461.2000

Cited by 335 publications

(281 citation statements)

References 63 publications

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“…The inhibitory effect of LY294002 on the level of Bad Ser112 phosphorylation is noteworthy, because it indicates that Akt-mediated phosphorylation of Ser136 precedes the phosphorylation of Ser112, the latter of which is assumed to be caused by RSK1, PAK1 or PKA [30][31][32]. PAK1 has been found to phosphorylate Bad at Ser136 and 112 and to protect fibroblasts and FL5.12 lymphoid progenitor cells from apoptosis [32].…”

Section: Doxorubicin-induced P38 Mapk Activation Negatively Regulatesmentioning

confidence: 99%

“…PAK1 has been found to phosphorylate Bad at Ser136 and 112 and to protect fibroblasts and FL5.12 lymphoid progenitor cells from apoptosis [32]. PAK1 can be activated by the small GTPases Rac and Cdc42, and either of those GTPases can be activated by inhibition of PI3-K, which may explain the weak effect of LY294002 treatment on phosphorylation of Bad.…”

Section: Doxorubicin-induced P38 Mapk Activation Negatively Regulatesmentioning

confidence: 99%

“…Upon dephosphorylation, Bad translocates to the mitochondria, where it associates primarily with Bcl-xL but also with Bcl-2, and thereby promotes apoptosis [28,29]. Cytokine-dependent phosphorylation of Bad has been reported to involve several kinases, such as Akt, protein kinase A (PKA), RSK1 (p90 ribosomal S6 kinase1), p70S6 kinase, and PAK1 [21,[30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

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p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

Grethe¹,

Coltella²,

Pörn-Ares³

2006

Biochemical and Biophysical Research Communications

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Doxorubicin is the anthracycline with the widest spectrum of antitumor activity, and it has been shown that the antitumor activity is mediated in vivo by selective triggering of apoptosis in proliferating endothelial cells. We studied cultured human endothelial cells and observed that doxorubicin-induced apoptosis was mediated by p38 mitogen-activated protein kinase (MAPK). Doxorubicin-provoked apoptosis was significantly inhibited by expression of dominant negative p38 MAPK or pharmacological inhibition with SB203580.Furthermore, blocking phosphatidylinositol-3-kinase/Akt signaling significantly increased doxorubicin-induced caspase-3 activity and cell death, indicating that Akt is a survival factor in this system. Notably, we also found that doxorubicin-provoked apoptosis included p38 MAPK-mediated inhibition of Akt and Bad phosphorylation. Furthermore, doxorubicinstimulated phosphorylation of Bad in cells expressing dominant negative p38 MAPK was impeded by the inhibition of PI3-K. In addition to the impact on Bad phosphorylation, doxorubicin-treatment caused p38 MAPK-dependent downregulation of Bcl-xL protein.

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Section: Doxorubicin-induced P38 Mapk Activation Negatively Regulatesmentioning

confidence: 99%

Section: Doxorubicin-induced P38 Mapk Activation Negatively Regulatesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

Grethe¹,

Coltella²,

Pörn-Ares³

2006

Biochemical and Biophysical Research Communications

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“…15 The cytotoxic effects of BAD are controlled by mechanisms that regulate its phosphorylation on at least two distinct serine residues, S112 and S136. [16][17][18] Previously, we showed that phosphorylation at either site is sufficient to protect prostate cancer cells from apoptosis. [19][20][21] We also showed that BAD promotes prostate tumor growth in mouse models.…”

mentioning

confidence: 99%

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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“…When Bad is serine phosphorylated on these functional residues, its proapoptotic function is suppressed by increasing its association with 14-3-3z and by decreasing its association with bcl-xL or bcl-2 at the mitochondrial membrane. 14,[24][25][26] Thus, B2 overexpression increases the threshold for mitochondrial release of sequestered apoptogenic proteins (cytochrome c and AIF) and markedly reduces apoptosis during serum starvation or staurosporine treatment.…”

Section: Discussionmentioning

confidence: 98%

A novel cellular survival factor – the B2 subunit of vacuolar H+-ATPase inhibits apoptosis

Yang

Krishnan

et al. 2006

Cell Death Differ

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The ubiquitous vacuolar H þ -ATPase, a multisubunit proton pump, is essential for intraorganellar acidification. Disruption of its function leads to disturbances of organelle function and cell death. Here, we report that overexpression of the B2 subunit of the H þ -ATPase inhibits apoptosis. This antiapoptotic effect is not mediated by an increase in H þ -ATPase activity but through activation of the Ras-mitogen-activated protein kinase (MAPK)-signaling pathway that results in the serine phosphorylation of Bad at residues 112 and 155. Increased Bad phosphorylation reduces its translocation to mitochondria, limits the release of mitochondrial cytochrome c and apoptosis-inducing factor and increases the resistance of the B2 overexpressing cells to apoptosis. Screening experiments of kinase inhibitors, including inhibitors of cAMP-activated protein kinase, protein kinase C, protein kinase B, (MAPK/extracellular signal-regulated (ERK) kinase) MEK and Ste-MEK1 13 , a cell permeable ERK activation inhibitor peptide, revealed that the B2 subunit of H þ -ATPase acts upstream of MEK activation in the MEK/ERK pathway to ameliorate apoptosis.

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p21-Activated Kinase 1 Phosphorylates the Death Agonist Bad and Protects Cells from Apoptosis

Abstract: Bad is a critical regulatory component of the intrinsic cell death machinery that exerts its death-promoting

Cited by 335 publications

References 63 publications

p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

A novel cellular survival factor – the B2 subunit of vacuolar H+-ATPase inhibits apoptosis

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