Identification of a novel Bcl-xL phosphorylation site regulating the sensitivity of taxol- or 2-methoxyestradiol-induced apoptosis.
Bcl-xL, a close homolog of Bcl2, is an important regulator of apoptosis and is overexpressed in human cancer. Phosphorylation of Bcl-xL can be induced by microtubule-damaging drugs such as taxol or 2-methoxyestradiol (2-ME). By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-ME-induced Bcl-xL phosphorylation in prostate cancer cells. Further studies with the inhibitor of Jun kinase (JNK) and phosphorylation null mutant of Bcl-xL reveal the augmentative role of JNK-mediated Bcl-xL phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of Bcl-xL by stress response kinase signaling might oppose the anti-apoptotic function of Bcl-xL to permit prostate cancer cells to die by apoptosis.
Basu
Aruna
A
Department of Research, Pharmacology, Ireland Cancer Center, MetroHealth Medical Center, Case Western Reserve University, R456, Rammelkamp Building, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.
Haldar
Subrata
S
D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D017931:DNA Primers; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D017931:DNA Primers; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D004958:Estradiol; D000077584:2-Methoxyestradiol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel