Our growth regulation research has been concerned with oncogenes and tumor suppressor genes as positive and negative regulators of normal and neoplastic growth. The main current project is concerned with a tumor suppressor gene family, DLC1-3, and the targets that it regulates. DLC1 is inactivated in a variety of tumors, but many aspects of it mechanism of action remain poorly understood. It negatively regulates Rho, via its Rho-GAP activity, but it is likely to encode other activities, as other Rho-GAPs are not known to be inactivated in cancer. We have previously determined that DLC1 interacts with members of the tensin gene family, via a region of DLC1 for which no function had been previously identified, and have shown this interaction contributes to the growth suppressor activity of DLC1. In collaborative studies, we have found that the Rho-GAP domain of DLC1 interacts with p120-Ras-GAP and interferes with the Rho-GAP activity of DLC1. We are currently trying to identify other activities of DLC1 to understand its mechanism of action better and to more fully substantiate our hypothesis that DLC1 is frequently inactivated in cancer because it encodes a multifunctional protein. Given the biological importance of the interaction between DLC1 and tensin, we have explored the role of this gene family (tensin1-4) in tumors. Tensin-3 was found to make a potent contribution to the oncogenicity of cell lines from non-small cell lung cancer (NSCLC), breast cancer, and melanoma, as well as from a transgenic mouse breast cancer model. The tensin-3 SH2 domain has the previously undescribed characteristic of its tyrosines being phosphorylated, by Src, and this phosphorylation contributes to the ability of some pro-oncogenic ligands, such as FAK and p130Cas, to bind the SH2 domain. Mutation of the the tyrosines in the SH2 domain reduces their binding and the biological activity of tensin-3. We have also identified negative regulation of the activity of Rho GTPase family proteins, Cdc42 and RhoA, as a new mechanism by which E-cadherin can negatively regulate the neoplastic growth of NSCLC lines. In each line studied, the predominantly active Rho GTPase family member Cdc42 or RhoA contributed to the oncogenic properties of the line and was potently regulated by E-cadherin.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Collins, Francis S; Anderson, James M; Austin, Christopher P et al. (2016) Basic science: Bedrock of progress. Science 351:1405
Durkin, Marian E; Qian, Xiaolan; Popescu, Nicholas C et al. (2013) Isolation of Mouse Embryo Fibroblasts. Bio Protoc 3:
Du, Xiaoli; Qian, Xiaolan; Papageorge, Alex et al. (2012) Functional interaction of tumor suppressor DLC1 and caveolin-1 in cancer cells. Cancer Res 72:4405-16
Li, Guorong; Du, Xiaoli; Vass, William C et al. (2011) Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK). Proc Natl Acad Sci U S A 108:17129-34
de la Luz Sierra, Maria; Sakakibara, Shuhei; Gasperini, Paola et al. (2010) The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1. Blood 115:3970-9
Asnaghi, L; Vass, W C; Quadri, R et al. (2010) E-cadherin negatively regulates neoplastic growth in non-small cell lung cancer: role of Rho GTPases. Oncogene 29:2760-71
Yang, X-Y; Guan, M; Vigil, D et al. (2009) p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. Oncogene 28:1401-9
Qian, Xiaolan; Li, Guorong; Vass, William C et al. (2009) The Tensin-3 protein, including its SH2 domain, is phosphorylated by Src and contributes to tumorigenesis and metastasis. Cancer Cell 16:246-58