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Proc Natl Acad Sci U S A. 2013 Oct 15;110(42):16868-73. doi: 10.1073/pnas.1306358110. Epub 2013 Sep 30.

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

Author information

1
Lineberger Comprehensive Cancer Center, Department of Pharmacology, and Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.

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 CRL4A-FBXW5-associated oncogenesis and regulation of RhoA signaling.

KEYWORDS:

Rho GTPase-activating protein 7; Rho-selective GTPase-activating protein; STARD12

PMID:
24082123
PMCID:
PMC3801067
DOI:
10.1073/pnas.1306358110
[Indexed for MEDLINE]
Free PMC Article

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