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

• Published in: Oncogene Vol. 23; no. 31; pp. 5301 - 5315
• Main Authors: Domina, Aaron M, Vrana, Julie A, Gregory, Mark A, Hann, Stephen R, Craig, Ruth W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.07.2004; Nature Publishing; Nature Publishing Group
• Subjects: Acetic acid; Acids; Amino Acid Sequence; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Binding Sites; Biological and medical sciences; Cancer; Carcinogens; Cell activation; Cell Biology; Cell death; Cell Line, Tumor; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; CHO Cells; Cricetinae; Cytotoxicity; Dogs; Dose-Response Relationship, Drug; Electrophoretic mobility; Enzyme Activation; Enzyme Inhibitors - pharmacology; Extracellular signal-regulated kinase; Fundamental and applied biological sciences. Psychology; Gene regulation; Growth factors; Human Genetics; Humans; Internal Medicine; Kinases; MAP Kinase Signaling System; Mcl-1 protein; Medicine; Medicine & Public Health; Mice; Microtubules; Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; Molecular Sequence Data; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - chemistry; Neoplasm Proteins - metabolism; Okadaic acid; Okadaic Acid - pharmacology; Oncology; original-paper; Paclitaxel; Paclitaxel - pharmacology; Peptide Mapping; Phosphatase; Phosphorylation; Post-transcription; Post-translation; Precipitin Tests; Protein kinase C; Protein Kinase C - metabolism; Protein Structure, Tertiary; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction; Tetradecanoylphorbol Acetate; Threonine - chemistry; Time Factors; Transfection; Translation; Tumor necrosis factor-TNF; Tumorigenesis; 12-O-tetradecanoylphorbol 13-acetate; protein phosphatase 1/2A; BCL2; taxol; mitogen activated protein kinase; protein phosphorylation; MCL1; extracellular signal regulated kinase; Phosphorylation; Extracellular signal-regulated protein kinase; Enzyme; Phosphoprotein phosphatase; Phosphoric monoester hydrolases; Mitogen-activated protein kinase; Cytotoxicity; Esterases; Activation; Acetate; Carcinogenesis; Protein; Pest; C-Onc gene; Hydrolases; Protooncogene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207692

BCL2 family members are subject to regulation at multiple levels, providing checks on their ability to contribute to tumorigenesis. However, findings on post-translational 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 ERK-inducible versus ERK-independent sites.