Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 42, Pages 16868-16873Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1306358110
Keywords
Rho-selective GTPase-activating protein; Rho GTPase-activating protein 7; STARD12
Categories
Funding
- National Cancer Institute [3P30CA016086, CA129610, CA130940]
- National Institute of Environmental Health Sciences [3P30ES010126]
- Department of Defense [W81XWH-09-2-0042]
- University of North Carolina University Cancer Research Fund
- Susan Komen postdoctoral fellowship
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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.
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