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

Tai Young Kim, Sarah Jackson, Yue Xiong, Timothy G. Whitsett, Janine R. Lobello, Glen J. Weiss, Nhan Le Tran, Yung Jue Bang, Channing J. Der

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 nonsmall 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 RhoAGTP 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 CRL4AFBXW5- associated oncogenesis and regulation of RhoA signaling.

Original languageEnglish
Pages (from-to)16868-16873
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number42
DOIs
StatePublished - 15 Oct 2013

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Cullin Proteins
Non-Small Cell Lung Carcinoma
rhoA GTP-Binding Protein
Growth
GTPase-Activating Proteins
Neoplasms
Ligases
Ubiquitin
Tumor Cell Line
Epigenomics
Small Interfering RNA
Carcinogenesis
Proteins
Cell Line
Messenger RNA
Genes
rho GTPase-activating protein

Keywords

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

Cite this

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. / CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 42. pp. 16868-16873.
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CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 42, 15.10.2013, p. 16868-16873.

Research output: Contribution to journalArticle

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AU - Kim, Tai Young

AU - Jackson, Sarah

AU - Xiong, Yue

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AU - Lobello, Janine R.

AU - Weiss, Glen J.

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AU - Bang, Yung Jue

AU - Der, Channing J.

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