RACK1 and CIS Mediate the Degradation of BimEL in Cancer Cells
Copyright policy )RACK1 and CIS Mediate the Degradation of BimEL in Cancer Cells
RACK1 is a 7-WD motif-containing protein with numerous downstream effectors regulating various cellular functions. Using a yeast two-hybrid screen, we identified dynein light chain 1 as a novel interacting partner of RACK1. Additionally, we demonstrated that RACK1 formed a complex with DLC1 and Bim, specifically BimEL, in the presence of apoptotic agents. Upon paclitaxel treatment, RACK1, DLC1, and CIS mediated the degradation of BimEL through the ElonginB/C-Cullin2-CIS ubiquitin-protein isopeptide ligase complex. We further showed that RACK1 conferred paclitaxel resistance to breast cancer cells in vitro and in vivo. Finally, we observed an inverse correlation between CIS and BimEL levels in both ovarian and breast cancer cell lines and specimens. Our study suggests a role of RACK1 in protecting cancer cells from apoptosis by regulating the degradation of BimEL, which together with CIS could play an important role of drug resistance in chemotherapy.
- The University of Texas Health Science Center at Houston United States
- The University of Texas MD Anderson Cancer Center United States
- Moffitt Cancer Center United States
- The University of Texas System United States
- Icahn School of Medicine at Mount Sinai United States
Mice, Inbred BALB C, Bcl-2-Like Protein 11, Neuropeptides, Membrane Proteins, Mice, Nude, Apoptosis, Receptors, Cell Surface, Suppressor of Cytokine Signaling Proteins, Receptors for Activated C Kinase, Models, Biological, Neoplasm Proteins, Mice, Drug Resistance, Neoplasm, GTP-Binding Proteins, Neoplasms, Proto-Oncogene Proteins, Animals, Humans, Apoptosis Regulatory Proteins
Mice, Inbred BALB C, Bcl-2-Like Protein 11, Neuropeptides, Membrane Proteins, Mice, Nude, Apoptosis, Receptors, Cell Surface, Suppressor of Cytokine Signaling Proteins, Receptors for Activated C Kinase, Models, Biological, Neoplasm Proteins, Mice, Drug Resistance, Neoplasm, GTP-Binding Proteins, Neoplasms, Proto-Oncogene Proteins, Animals, Humans, Apoptosis Regulatory Proteins
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