RACK1 and CIS Mediate the Degradation of BimEL in Cancer Cells

• Published in: The Journal of biological chemistry Vol. 283; no. 24; pp. 16416 - 16426
• Main Authors: Zhang, Weizhou, Cheng, George Zhi, Gong, Jianli, Hermanto, Ulrich, Zong, Cong Susan, Chan, Joseph, Cheng, Jin Quan, Wang, Lu-Hai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.06.2008; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Drug Resistance, Neoplasm; GTP-Binding Proteins - metabolism; Humans; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neuropeptides - metabolism; Proto-Oncogene Proteins - metabolism; Receptors for Activated C Kinase; Receptors, Cell Surface - metabolism; Suppressor of Cytokine Signaling Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M802360200

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.