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Regulation
of Genomic Instability in Mammalian Cells
Our laboratory is interested in the regulation of genomic instability
in mammalian cells. These studies have led us to the investigation of
cell cycle checkpoint genes which are part of a signal transduction pathway
that governs a cell's response to environmental cues. We use genetic,
molecular, biochemical and cytogenetic techniques to study the cell biology
of tumor cell formation and progression in human cells.
Our initial studies demonstrated that while gene amplification, one type
of genomic instability, could be detected in tumor cells, it could not
be detected in normal cells. We identified the first set of genes which
controls this process in human cells. The tumor suppressor gene, p53,
prevents gene amplification in primary cells, essentially by acting as
part of a signal transduction pathway that senses genomic damage and allows
for the cell to halt cell cycle progression to increase chances for repair.
Knowledge of these control processes can be used in the diagnosis of cancer
or the identification of individuals that are predisposed to neoplasia.
We have begun screening studies to identify such individuals.
More recently, we have extended our studies to additional types of chromosomal
abnormalities, recombinations and aneuploidy. We would like to understand
how these processes are modulated in human cells so that it can be used
to increase therapeutic efficiency. Genomic instability is known to underlie
the processes of metastasis and the generation of drug-resistant tumor
cells, two events which impair cancer treatment.
Selected Publications:
Tlsty, T.D. (1990) Normal diploid human and rodent cells lack a detectable
frequency of gene amplification. P.N.A.S. 87, 3132-3135.
Tlsty, T.D., White, A. and Sanchez, J. (1992) Suppression of Gene Amplification
in Human Cell Hybrids. Science 255, 1425-1427.
Livingstone, L., White, A., Sprouse, J., Livanos, E. and Tlsty, T.D. (1992)
Altered Cell Cycle Arrest and Gene Amplification Potential Accompany Loss
of Wild-Type p53. Cell 70, 923-935.
White, A., Livanos, E. and Tlsty, T.D. (1994) Differential Disruption
of Genomic Integrity and Cell Cycle Regulation in Normal Human Fibroblasts
by the HPV Oncoproteins. Genes and Development 8, 666-677.
Tlsty, T.D., White, A., Livanos, E., Sage, M., Roelofs, H., Briot, A.
and Poulose, B. Genomic Integrity and the Genetics of Cancer. Cold Spring
Harbor Symposia on Quantitative Biology, Volume 59, pp. 265-275, 1994.
Antonio Gualberto, Ken Aldape, Krystyna Kozakiewicz, Thea Tlsty (1998)îAn
oncogenic form of p53 confers a dominant, gain-of-function phenotype that
disrupts spindle checkpoint controlî Proc. Natl. Acad. Sci. Vol. 95 5166-
5171.
Contact Information:
Email: ttlsty@itsa.ucsf.edu
Phone: 415/ 502-6115
Address: box 0506, Room HSW 425
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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