Bcl-2 Phosphorylation Required for Anti-apoptosis Function

Ito, Takahiko; Deng, Xingming; Carr, Boyd; May, W. Stratford

doi:10.1074/jbc.272.18.11671

Cited by 512 publications

(519 citation statements)

References 17 publications

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“…Western blot was performed by loading 50 mg of protein per lane on an 8-12% SDS-PAGE, followed by protein transfer to nitrocellulose membrane for analysis of specific protein(s). 44 Figure 6 Subcellular fractionation. Subcellular fractionation was performed to isolate HM, LM, cytosol and nuclear fractions as we described previously.…”

Section: Discussionmentioning

confidence: 99%

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Wang

Xie

et al. 2014

Cell Death Differ

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Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) Mcl-1 is an antiapoptotic molecule that is overexpressed in various types of cancers, including lung cancer, 1 leukemia, 2 lymphoma, 3 hepatocellular carcinoma 4 and so on. In addition to its antiapoptotic function, Mcl-1 is also an oncoprotein that promotes the development of cancer. 5 In contrast to other Bcl2 family members such as Bcl2 and Bcl-XL, Mcl-1 is unique in its short half-life (30 min-3 h) and short-term prosurvival function, which probably relates to the presence of a long proline-, glutamic acid-, serine-and threonine-rich (PEST) region upstream of the Bcl2 homology (BH) domain. 1 The mechanism(s) that stabilizes the Mcl-1 protein are critical for its long-term survival function. Mcl-1 protein can be phosphorylated at multiple sites that distinctly regulate Mcl-1 protein turnover. For example, extracellular signal-regulated kinase 1/2-mediated T163 site phosphorylation enhances the half-life and antiapoptotic function of Mcl-1. 1,6 In contrast, S159 phosphorylation by GSK-3b facilitates Mcl-1 ubiquitination and degradation to reduce its survival activity. 7 Ubiquitination and deubiquitination are two reversible processes that can control protein stability. E3 ligases and deubiquitinases (deubiquitinating enzymes (DUBs)) are two groups of regulatory enzymes that orchestrate the ubiquitination levels of target proteins in eukaryotic cells. 8 Recently, Mule and FBW7 have been identified as Mcl-1 ubiquitin E3 ligases that can directly induce polyubiquitination and degradation of Mcl-1. 9,10 Inversely, USP9X has been demonstrated as the Mcl-1 deubiquitinase that removes the Lys 48-linked polyubiquitin chains that normally mark Mcl-1 for proteasomal degradation, leading to stabilization of Mcl-1. 3 Therefore, the stability of Mcl-1 in cells is tightly regulated by its E3 ligases and deubiquitinase, which is dependent on Mcl-1 phosphorylation status. 3,11 Ku70 is a protein that binds to DNA double-strand break (DSB) ends and is required for the non-homologous endjoining pathway of DSB repair. 12-15 The Ku70 protein consists of three structural domains, including the N-terminal, central (that is, DNA binding) and C-terminal domains. 16,17 Ku70 usually heterodimerizes with Ku86, which forms a functional complex for DSB repair. By forming a bridge between the broken DNA ends, the Ku70/Ku86 heterodimer acts to structurally support and align the DNA ends, to protect them from degradation and to prevent promiscuous binding to unbroken DNA. Ku70/Ku86 effectively aligns the DNA, while still allowing access of polymerases, nucleases and ligases to the broken DNA ends to promote end joining. 18 In some cases, a fourth domain is present at the C terminus of Ku86, which binds to the DNA-dependent protein kinase catalytic subunit...

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Section: Discussionmentioning

confidence: 99%

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Wang

Xie

et al. 2014

Cell Death Differ

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“…In addition, the activation of the PI-3 kinase-AKT pathway regulates the expression of Bcl-x (Leverrier et al, 1999). Regulation of Bcl-x gene expression and of Bcl-2 phosphorylation via the Ras/MAP kinase pathway and a PKC dependent pathway have also been reported (Leverrier et al, 1997;Kinoshita et al, 1995b;Ito et al, 1997). Thus, the inhibition of STAT5 activity may not be su cient to induce apoptosis in presence of IL-3 in Ba/F3 cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, from our experiments, we cannot exclude that STAT5 regulates the phosphorylation of Bcl-2. Indeed, phosphorylation of Bcl-2 after IL-3 stimulation has been shown to contribute to the inhibition of apoptosis (Ito et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line

et al. 1999

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“…This loop region has distinctive lengths and primary sequences among BID, BAX, and the antiapoptotics BCL-2 and BCL-X L , and is believed to regulate their apoptotic functions. For example, phosphorylation within the loop region of BCL-2 differentially modulates its antiapoptotic activity depending upon the cellular context, 87,88 and caspasemediated cleavage at the loop can actually transform BCL-2 into a proapoptotic protein. 64 Caspase-8-mediated cleavage of BID within the unstructured loop results in exposure of the BH3 helix of tBID, 85,86 which is targeted to the mitochondria for apoptosis induction.…”

Section: Bcl-2 Family Form and Functionmentioning

confidence: 99%

BCL-2 in the crosshairs: tipping the balance of life and death

Walensky¹

2006

Cell Death Differ

225

175

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The discovery of B-cell lymphoma-2 (BCL-2) over 20 years ago revealed a new paradigm in cancer biology: the development and persistence of cancer can be driven by molecular roadblocks along the natural pathway to cell death. The subsequent identification of an expansive family of BCL-2 proteins provoked an intensive investigation of the interplay among these critical regulators of cell death. What emerged was a compelling tale of guardians and executioners, each participating in a molecular choreography that dictates cell fate. Ten years into the BCL-2 era, structural details defined how certain BCL-2 family proteins interact, and molecular targeting of the BCL-2 family has since become a pharmacological quest. Although many facets of BCL-2 family death signaling remain a mechanistic mystery, small molecules and peptides that effectively target BCL-2 are eliminating the roadblock to cell death, raising hopes for a medical breakthrough in cancer and other diseases of deregulated apoptosis.

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Bcl-2 Phosphorylation Required for Anti-apoptosis Function

Cited by 512 publications

References 17 publications

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis

IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line

BCL-2 in the crosshairs: tipping the balance of life and death

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