ZIA BC 008905 (ZIA) | |||
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Title | Tumor gene expression in vitro and in vivo | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Lowy, Douglas | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $365,992 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2013 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Metastasis (15.0%) |
Breast (20.0%) Cervical Cancer (30.0%) Lung (40.0%) Prostate (10.0%) |
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Research Type | |||
Cancer Initiation: Oncogenes and Tumor Suppressor Genes | |||
Abstract | |||
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 focused on the tumor suppressor gene DLC1 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 have been identifying 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. To this end, we have determined that DLC1 interacts with the focal adhesion kinase (FAK), talin, and caveolin-1 (CAV1). FAK is a pro-oncogenic cytoplasmic kinase, talin activates integrins by binding to the intracellular portion of beta-integrins, and CAV1 is a membrane-associated protein that is key component of caviolae. CAV1 usually functions as a tumor suppressor gene, but is pro-oncogenic in some tumor types. We found that FAK and talin bind to the same DLC1 sequence, an 8 amino acid sequence with homology to LD motifs in paxillin, which we have designated an LD-like motif. Mutation of the LD-like motif reduced the interaction between DLC1 and both FAK and talin as well as attenuating the ability of DLC1 to inhibit cell growth. The interaction between DLC1 and CAV1 has been localized to the StAR-related lipid transfer (START) domain of DLC1. This is the first partner identified for the start domain. As with the LD-like motif, mutation of the START domain decreased the binding between DLC1 and CAV1 and attenuated the growth inhibitory activity of DLC1. These studies therefore validate the hypothesis that DLC1 is a multifunctional protein whose biological activity depends both on its RhoGAP activity and its ability to bind a variety of signaling molecules. |