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Contact information Recent publications Laboratory of Molecular Biology |
Biography: Dr. Jhappan received her Ph.D. in Biochemistry from Georgetown University in 1986. Her Ph.D. research was carried out in the Laboratory of Molecular Oncolgy at the Frederick Cancer Research and Development Center centered on the mechanisms by which retroviruses are able to transduce host cellular sequences and incorporate them into their genomes. Her postdoctoral training was with Dr. Glenn Merlino in the Laboratory of Molecular Biology at the National Cancer Institute, NIH.Research: My general research interests as part of the Molecular Genetics Section have focused on the use of transgenic mice to study the role of certain growth factors such as TGF-alpha and TGF-beta1 in both normal mouse development as well as in disease pathogenesis. Transgenic mice harboring these factors have been generated in our lab by directly injecting cDNA sequences encoding growth factors under the control of specific promoter sequences into the pronucleus of single
cell embryos.Mice expressing the TGF-alpha transgene demonstrate a variety of lesions
including liver tumors and mammary tumors in parous females that are six
months old. In addition to these organs, TGF-alpha mice also demonstrate
stomach lesions reminiscent of Menetrier's disease, characterized by abnormal
thickening of the stomach wall caused by hyperplasia of the surface
epithelium. The TGF-alpha transgenic mouse skin has proven to be a useful
experimental model for analysis of signal transduction in carcinogenesis.
Multistage skin tumorigenesis in normal mice requires both initiation by
exposure to a mutagenic chemical, and promotion by nongenotoxic agents that
stimulate clonal expansion of initiated cells. The initiator
7,12-dimethylbenz[a]anthracene (DMBA) induces papillomas in mouse skin
promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA), of which over 90%
contain a characteristic A to T transversion in codon 61 of the
c-Ha-ras gene. We found that without promotion, DMBA induces a
variety of benign and malignant tumors in transgenic mouse skin, indicating
that TGF-alpha is functioning as an autonomous tumor promoter. Significantly,
more than half of these transgenic skin tumors had wild type c-Ha-ras
genes with greatly enhanced TGF-alpha transgene expression, strongly suggesting
that TGF-alpha is capable of circumventing the need for c-Ha-ras
mutations in DMBA-induced skin carcinogenesis. These results indicate that
TGF-alpha plays an important role in skin tumorigenesis, and demonstrate
that the TGF-alpha transgenic mouse constitutes a useful animal model for
studying human skin cancer.TGF-beta1 transgenic mice have also been generated where TGF-beta1 is expressed in the mammary gland under the control of the pregnancy induced whey-acidic protein promoter. Female mice expressing TGF-beta1 are unable to lactate due to the inhibition of the formation of lobuloalveolar structures and the suppression of production of endogenous milk protein. From this study, it is clear that TGF-beta1 plays an important role in the development and function of the mammary gland demonstrating TGF-beta1 may function in vivo as a developmental regulator. Current studies are underway to study transgenic mice harboring both TGF-alpha and TGF-b1 and these studies suggest that in the double transgenics TGF-beta1 acts as an inhibitor of mammary tumor formation typically seen in TGF-alpha mice.Collaborators on this research include Gilbert Smith, Ph.D., Laboratory
of Tumor Immunology and Biology, NCI and Anita Roberts, Ph.D., Laboratory of
Chemoprevention, NCI.Recent Publications: |
Contact Information: Laboratory of Molecular Biology,NCI, NIHBuilding 37, Room 2E2237 CONVENT DR MSC 4255BETHESDA MD 20892-4255Phone: 301-496-4620Fax:301-480-7618Email: cjhappan@helix.nih.gov
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