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Contact information Recent publications Curriculum vitae Laboratory of Molecular Biology |
Biography: Dr. Merlino received his Ph.D. in 1980 from the Department of Cellular and Molecular Biology at the University of Michigan. He currently serves as the NIH Ombudsman, and is on the editorial board of the American Journal of Pathology.Research: Eucaryotic cells communicate through an intricate network of signaling pathways designed to exquisitely regulate cellular activities such as growth, differentiation, migration and apoptosis. Signaling, and therefore biological response, is frequently initiated when specific peptide growth factors interact with high affinity cell surface receptors, many of which are powerful tyrosine kinases encoded by protooncogenes. The main goal of the Molecular Genetics Section is to use genetically engineered mice to determine how specific tyrosine kinase receptors (TKRs) regulate complex in vivo processes, such as embryonic development, and to determine how subverting their normal regulation induces tumorigenesis and/or facilitates metastatic dissemination. We have chosen the melanocyte as a model system to study TKRs because the melanocyte is unusual in its dependency for normal development and function on a multitude of TKRs, including the hepatocyte growth factor/scatter factor (HGF/SF) receptor Met, and the fibroblast growth factor (FGF) receptor (FGFR). Moreover, melanocytic tumors deserve extraordinary attention because they are appearing with increasing incidence and are among the most aggressive types of human cancer.HGF/SF is a multifunctional factor able to elicit mitogenic, motogenic and morphogenic responses in various c-ImetI expressing epithelial cells and in melanocytes. Furthermore, c-ImetI
is essential for normal embryogenesis, and has been implicated in the development of many human tumors, including malignant melanoma. We have determined that overexpressing an HGF/SF transgene in mice perturbs normal melanocyte development, and later induces cutaneous malignant melanoma with metastatic capability, a phenotype that is exceedingly rare in mice. Typically, these tumors showed both high expression of transgenic HGF/SF and enhanced Met expression and kinase activity, indicating that the creation and selection of cells expressing HGF/SF-Met autocrine signal transduction loops is the mechanistic basis of tumorigenesis in this transgenic model. Interestingly, in those rare melanomas without HGF/SF-Met autocrine loops, both basic FGF and its receptor were overexpressed, suggesting that these two TKRs may serve some critical overlapping function in melanocytic tumorigenesis. Currently, strategies involving transplants and cell lines derived from tumors from these HGF/SF transgenic mice are being adopted to ascertain the precise roles of TKR signaling in melanoma formation and progression. In addition, we will examine if TKRs can interact synergistically with the p16ink4a tumor suppressor in melanoma development, and if so, by what mechanism.
We are attempting to develop novel, therapeutically useful TKR-based reagents targeted to melanomas. Natural splice variants of HGF/SF are being tested in vivo to assess their ability to antagonize the oncogenic activities of HGF/SF in our transgenic mice. We are also testing the ability of secreted kinase-deficient TKR/Fc chimeras to effectively disrupt in vivo function by acting as dominant-negative agents. We recently showed that mid-gestational expression of an FGFR/Fc chimera in transgenic embryos caused agenesis or severe dysgenesis of a multitude of organs and structures, indicating that FGFR signaling is broadly required for organogenesis and patterning, and proving that such soluble TKR mutants can be highly effective as dominant-negative agents in vivo.Working independently within my Section, Dr. Chamelli Jhappan is focusing her research on DNA-dependent protein kinase (DNA-PK), a molecule composed of DNA-binding Ku70 and Ku86 components as well as the large DNA-dependent catalytic subunit (DNA-PKcs). DNA-PKcs is a member of the phosphatidylinositol 3-kinase (PI3K) family which includes molecules involved in DNA-damage response such as IATMI, mutated in the human autosomal recessive disorder ataxia telangiectasia. One approach to addressing the true function of DNA-PKcs in cellular DNA damage response is to study the consequences of complete inactivation of this molecule in mice. To this end, Dr. Jhappan has demonstrated that IDNA-PKcsI is inactivated in the IslipI transgenic mice she generated as a consequence of an insertional mutation. The IslipI mouse lacks detectable levels of DNA-PKcs mRNA, cannot rearrange its antigen receptors and uniformly develops lymphoblastic lymphomas. The latter strongly suggests that in mice, IDNA-PKcsI acts as a T-cell tumor suppressor and since it is involved in DNA repair, likely belongs to the "caretaker" class of tumor suppressor genes which include IATM, BRCA1I and IBRCA2.Collaborators include William LaRochelle, Ph.D., Susan Mackem, M.D., William Pavan, Ph.D., all at the NIH.Recent Publications: |
Contact Information: Laboratory of Molecular Biology,NCI, NIHBuilding 37, Room 2E2437 CONVENT DR MSC 4255BETHESDA MD 20892-4255Phone: 301-496-4270Fax:301-480-7618Email: gmerlino@helix.nih.gov
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