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CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth

Cited 39 time in Web of Science Cited 39 time in Scopus
Authors
Kim, Tai Young; Jackson, Sarah; Xiong, Yue; Whitsett, Timothy G.; Lobello, Janine R.; Weiss, Glen J.; Le Tran, Nhan; Bang, Yung-Jue; Der, Channing J.
Issue Date
2013-10
Citation
Proceedings of the National Academy of Sciences of the United States of America, Vol.110 No.42, pp.16868-16873
Keywords
Rho-selective GTPase-activating proteinRho GTPase-activating protein 7STARD12
Abstract
DLC1 encodes a RhoA GTPase-activating protein and tumor suppressor lost in cancer by genomic deletion or epigenetic silencing and loss of DLC1 gene transcription. We unexpectedly identified non-small cell lung cancer (NSCLC) cell lines and tumor tissue that expressed DLC1 mRNA yet lacked DLC1 protein expression. We determined that DLC1 was ubiquitinated and degraded by cullin 4A-RING ubiquitin ligase (CRL4A) complex interaction with DDB1 and the FBXW5 substrate receptor. siRNA-mediated suppression of cullin 4A, DDB1, or FBXW5 expression restored DLC1 protein expression in NSCLC cell lines. FBXW5 suppression-induced DLC1 reexpression was associated with a reduction in the levels of activated RhoA-GTP and in RhoA effector signaling. Finally, FBXW5 suppression caused a DLC1-dependent decrease in NSCLC anchorage-dependent and -independent proliferation. In summary, we identify a posttranslational mechanism for loss of DLC1 and a linkage between CRL4-AFBXW5-associated oncogenesis and regulation of RhoA signaling.
ISSN
0027-8424
URI
https://hdl.handle.net/10371/173152
DOI
https://doi.org/10.1073/pnas.1306358110
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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