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Phosphatase PP2A enhances MCL-1 protein half-life in multiple myeloma cells.
- Source :
-
Cell death & disease [Cell Death Dis] 2021 Mar 03; Vol. 12 (3), pp. 229. Date of Electronic Publication: 2021 Mar 03. - Publication Year :
- 2021
-
Abstract
- Multiple myeloma (MM), a treatable but incurable malignancy, is characterized by the growth of clonal plasma cells in protective niches in the bone marrow. MM cells depend on expression of BCL-2 family proteins, in particular MCL-1, for survival. The regulation of MCL-1 is complex and cell type-dependent. Unraveling the exact mechanism by which MCL-1 is overexpressed in MM may provide new therapeutic strategies for inhibition in malignant cells, preferably limiting side effects in healthy cells. In this study, we reveal that one cause of overexpression could be stabilization of the MCL-1 protein. We demonstrate this in a subset of MM and diffuse large B cell lymphoma (DLBCL) cell lines and MM patient samples. We applied a phosphatase siRNA screen to identify phosphatases responsible for MCL-1 stabilization in MM, and revealed PP2A as the MCL-1 stabilizing phosphatase. Using the PP2A inhibitor okadaic acid, we validated that PP2A dephosphorylates MCL-1 at Ser159 and/or Thr163, and thereby stabilizes MCL-1 in MM cells with long MCL-1 half-life, but not in DLBCL cells. Combined kinase and phosphatase inhibition experiments suggest that the MCL-1 half-life in MM is regulated by the counteracting functions of JNK and PP2A. These findings increase the understanding of the mechanisms by which MCL-1 is post-translationally regulated, which may provide novel strategies to inhibit MCL-1 in MM cells.
- Subjects :
- Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Half-Life
Humans
JNK Mitogen-Activated Protein Kinases metabolism
Lymphoma, Large B-Cell, Diffuse genetics
Lymphoma, Large B-Cell, Diffuse pathology
Multiple Myeloma genetics
Multiple Myeloma pathology
Myeloid Cell Leukemia Sequence 1 Protein genetics
Phosphorylation
Protein Phosphatase 2 genetics
Protein Stability
Proteolysis
Lymphoma, Large B-Cell, Diffuse enzymology
Multiple Myeloma enzymology
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Protein Phosphatase 2 metabolism
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 12
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 33658484
- Full Text :
- https://doi.org/10.1038/s41419-020-03351-7