Physical and Functional Interaction between Myeloid Cell Leukemia 1 Protein (MCL1) and Fortilin
Open Access
- 1 October 2002
- journal article
- Published by Elsevier BV
- Vol. 277 (40), 37430-37438
- https://doi.org/10.1074/jbc.m207413200
Abstract
Myeloid cell leukemia 1 protein (MCL1) is an anti-apoptotic protein that is structurally related to Bcl-2. Unlike other Bcl-2 family proteins that are constitutively expressed, MCL1 is inducibly expressed in cells that are recently exposed to growth and differentiation stimuli. Here, we report the identification of fortilin as a novel MCL1-interacting protein by screening of a yeast two-hybrid library with MCL1 as bait. Fortilin specifically interacted with MCL1 both in vitro andin vivo. The intracellular localization of fortilin was predominantly nuclear and identical to that of MCL1, as shown by immunostaining and confocal microscopy analysis. Fortilin, like MCL1, was rapidly inducible in serum-stimulated human aortic vascular smooth muscle cells. Although the depletion of intracellular fortilin by small interfering RNA (siRNA) against fortilin (siRNA-fortilin) did not affect intracellular MCL1 level, the depletion of intracellular MCL1 by siRNA-MCL1 was associated with the significant reduction of the fortilin protein level, without affecting the fortilin transcript numbers. In addition, a pulse-chase experiment showed that the depletion of MCL1 by siRNA-MCL1 was associated with the rapid degradation of fortilin protein, which was found quite stable in the presence of MCL1. Furthermore, the half-life of fortilinR21A, a point mutant of fortilin lacking the binding to MCL1, was significantly shorter than that of wild-type fortilin as shown by a pulse-chase experiment. These data suggest that MCL1, in addition to being an anti-apoptotic molecule, serves as a chaperone of fortilin, binding and stabilizing fortilin in vivo. Taken together with our previous observation that fortilin overexpression prevents cells from undergoing apoptosis (Li, F., Zhang, D., and Fujise, K. (2001) J. Biol. Chem. 276, 47542–47549), it is likely that MCL1, an anti-apoptotic protein inducible by growth and differentiation stimuli, stabilizes another anti-apoptotic protein fortilin maximizing the prosurvival environment in cells.Keywords
This publication has 28 references indexed in Scilit:
- Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cellsBlood, 2000
- GM-CSF RESCUES TF-1 CELLS FROM GROWTH FACTOR WITHDRAWAL-INDUCED, BUT NOT DIFFERENTIATION-INDUCED APOPTOSIS: THE ROLE OF BCL-2 AND MCL-1Cytokine, 1999
- The Antiapoptotic Gene mcl-1 Is Up-Regulated by the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway through a Transcription Factor Complex Containing CREBMolecular and Cellular Biology, 1999
- Activation of the CAMP signaling pathway increases apoptosis in human B-precursor cells and is associated with downregulation of Mcl-1 expressionJournal of Cellular Physiology, 1999
- Mcl-1 in Transgenic Mice Promotes Survival in a Spectrum of Hematopoietic Cell Types and Immortalization in the Myeloid LineageBlood, 1998
- Mcl-1 Expression in Human Neutrophils: Regulation by Cytokines and Correlation With Cell SurvivalBlood, 1998
- The Bcl-2 Protein Family: Arbiters of Cell SurvivalScience, 1998
- mcl-1 Is an Immediate-Early Gene Activated by the Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Signaling Pathway and Is One Component of the GM-CSF Viability ResponseMolecular and Cellular Biology, 1998
- BCL-2 and MCL-1 Expression in Chinese Hamster Ovary Cells Inhibits Intracellular Acidification and Apoptosis Induced by StaurosporineExperimental Cell Research, 1996
- MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2.Proceedings of the National Academy of Sciences of the United States of America, 1993