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

Oncogene. 2004 Jul 8;23(31):5301-15. 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis
  • Binding Sites
  • CHO Cells
  • Carcinogens
  • Cell Line, Tumor
  • Cell Survival
  • Cricetinae
  • Dogs
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Humans
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / metabolism*
  • Okadaic Acid / pharmacology
  • Paclitaxel / pharmacology
  • Peptide Mapping
  • Phosphorylation
  • Precipitin Tests
  • Protein Kinase C / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Tetradecanoylphorbol Acetate
  • Threonine / chemistry
  • Time Factors
  • Transfection


  • Antineoplastic Agents, Phytogenic
  • Carcinogens
  • Enzyme Inhibitors
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Okadaic Acid
  • Threonine
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate
  • Paclitaxel