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.
Zhang
Weizhou
W
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Cheng
George Zhi
GZ
Gong
Jianli
J
Hermanto
Ulrich
U
Zong
Cong Susan
CS
Chan
Joseph
J
Cheng
Jin Quan
JQ
Wang
Lu-Hai
LH
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D019008:Drug Resistance, Neoplasm; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy; D009479:Neuropeptides / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D019204:GTP-Binding Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D050826:Suppressor of Cytokine Signaling Proteins; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C419368:RACK1 protein, human; C090294:RACK1 protein, mouse