Inducer-and cell type-specific regulation of antiapoptotic MCL1 in myeloid leukemia and multiple myeloma cells exposed to differentiation-inducing or microtubule-disrupting agents.
The antiapoptotic BCL2 family member MCL1 is rapidly upregulated upon exposure of ML-1 myeloid leukemia cells to either differentiation-inducing phorbol 12'-myristate 13'-acetate (PMA) or chemotherapeutic microtubule disrupting agents (MTDAs). This report examined how signaling for MCL1 upregulation is coupled to these two different phenotypic changes, and tested for upregulation in other hematopoietic cancers. With PMA, ERK stimulated MCL1 mRNA expression and ML-1 cell differentiation, and ERK additionally stabilized expression of the MCL1 protein. However, with MTDAs, transient ERK and ensuing JNK activation contributed to initial MCL1 upregulation and viability-retention, but sustained JNK activation eventually resulted in cell death. MCL1 was upregulated by PMA in THP-1 and U937 myeloid leukemia cells, but by MTDAs only in THP-1 cells. MCL1 expression was constitutively elevated in multiple myeloma cell lines, and was not affected by PMA/ERK or MTDAs. Thus, MCL1 expression level and sensitivity to regulation are important considerations in selecting approaches for targeting this antiapoptotic gene product to kill cancer cells.
Vrana
Julie A
JA
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
Cleaveland
Emily S
ES
Eastman
Alan
A
Craig
Ruth W
RW
D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000503:physiopathology*; D008870:Microtubules / Q000187:drug effects; D009101:Multiple Myeloma / Q000503:physiopathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology; D020298:U937 Cells; D014747:Vinblastine / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050257:Tubulin Modulators; D014747:Vinblastine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate