BAD Ser-155 Phosphorylation Regulates BAD/Bcl-XL Interaction and Cell Survival

Tan, Yi; Demeter, Matthew R.; Ruan, Hong; Comb, Michael J.

doi:10.1074/jbc.m004199200

Cited by 284 publications

(223 citation statements)

References 34 publications

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“…The cell viability was judged by measuring the luciferase activity in the cell lysates as described. 19,34 The survival of BAD2SA-expressing CSCs was substantially decreased compared with BADwt-CSCs ( Figure 2d). As CSCs expressed elevated levels of antiapoptotic BCL-XL as shown in Figure 1h, and endogenous BAD was still phosphorylated in BAD2SA-CSCs (Figure 2e), we tested whether BH3-mimetic can further sensitize CSCs to BAD2SA-mediated cell death.…”

Section: Resultsmentioning

confidence: 97%

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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Section: Resultsmentioning

confidence: 97%

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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“…Bad is inactivated by phosphorylation through the MAPK pathway, with ERK phosphorylating p90Rsk, which in turn phosphorylates Bad at amino acid (aa) 75 (aa112 in mice) 292 . Akt can also phosphorylate Bad at aa999 (aa136 nin mice) 293 and PKA can phosphorylate it at aa118 (aa155 in mice) 294 . Caspase-8 mediated proteolysis of Bid results in active truncated Bid (t-Bid) which acts as the bridge between the extrinsic and intrinsic apoptotic pathways (Figure 1.5) 295 .…”

Section: Regulation Of the Bh3-only Proteinsmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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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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BAD Ser-155 Phosphorylation Regulates BAD/Bcl-XL Interaction and Cell Survival

Cited by 284 publications

References 34 publications

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

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

Role of the pro-survival molecule Bfl-1 in melanoma

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

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