Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Drug Resistance, Neoplasm
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GTP-Binding Proteins / metabolism*
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Humans
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Models, Biological
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Neoplasm Proteins / metabolism*
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Neoplasms / drug therapy
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Neuropeptides / metabolism*
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Proto-Oncogene Proteins / metabolism
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Receptors for Activated C Kinase
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Receptors, Cell Surface / metabolism*
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Suppressor of Cytokine Signaling Proteins / metabolism*
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Membrane Proteins
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Neoplasm Proteins
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Neuropeptides
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Proto-Oncogene Proteins
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RACK1 protein, human
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RACK1 protein, mouse
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Receptors for Activated C Kinase
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Receptors, Cell Surface
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Suppressor of Cytokine Signaling Proteins
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cytokine inducible SH2-containing protein
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GTP-Binding Proteins