JAMES R. SMITH, PH.D.
Professor of Pathology
Ewing Halsell Distinguished Chair in Aging Research

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Department of Pathology – Mail Code 7750
The University of Texas Health Science Center
7703 Floyd Curl Drive
San Antonio, Texas 78229-3900
INFORMATION
Email: smithjr@uthscsa.edu
Phone: (210) 562-5067   Fax: (210) 562-5028


EDUCATION
1970 Ph.D., Mol. Biophysics, Yale University.
1968 M.Ph., Mol. Biophysics, Yale University.
1965 Biophysics, U. Arizona Tucson
1963 B.S., Physics, Univ. Missouri at Rolla
 
TRAINING
1970-72 Postdoctoral Trainee, Stanford Univ.
1972-75 Postdoctoral Trainee, UC Berkeley
 
HONORS AND AWARDS
1983 Heinz Karger Award Prize on Cellular Aging
1994 Glen Foundation Award of the Gerontological Society of America
1994 Allied Signal Achievement Award for Excellence in Aging Research
1994 Michael E. Debakey Award for Excellence in Research
1997 Kesten Memorial Lectureship Award (with Dr. Olivia M. Pereira-Smith)
1997 9th Annual Robert R. Kohn Memorial Lecture, Sept. 23, , Case Western Reserve University, Cleveland, OH.


PROFESSIONAL SOCIETY MEMBERSHIPS
1. Gerontological Society
2. Tissue Culture Association
3. American Association for the Advancement of Science


RESEARCH INTERESTS
   My laboratory is currently studying the epigenetic aspects of in vitro cellular aging.
   Normal cells derived from humans and other animals exhibit a limited division potential in culture. After achieving a certain number of population doublings, depending on the species and age of the donor, the cells stop dividing. However, the cells do not die but remain viable for up to three years. This phenomenon is widely considered aging at the cellular level. As cells age in culture their telomeres become shorter (because they do not express the enzyme telomerase). When the telomeres become “critically” short, the cells are triggered to enter the senescence state. However, these cells can be “immortalized” by expression of the enzyme telomerase. Telomere shortening has emerged as a major candidate for a counting mechanism that determines how many time a cell can divide. However, the way that short telomeres can effect the onset of senescence is not understood.
   The Cdk inhibitor p21 is necessary for cells to enter the normal senescence state. However, pathway by which short telomeres induce p21 and, therefore, senescence has not been elucidated. Nor have the processes that result in significant changes in gene expression during cellular senescence. Therefore, it is highly likely that other processes, in addition to telomere shortening, are involved in cellular aging.
   As cells age in culture, they lose methyl-cytosine from their genomic DNA. Changes in DNA methylation can have profound effects on the pattern of gene expression. Interestingly, it has recently been reported that simply decreasing DNA methyltransferase (DNA MeTase) activity causes induction of p21, without changes in DNA methylation. Therefore, the observed changes in MeTase activity and/or DNA methylation could account for the changes in gene expression seen with cellular aging. A recent observation in our laboratory, that cells expressing hTERT maintain DNA MeTase provides a possible explanation for the prevention, by hTERT, of changes in gene expression that normally occur with cellular aging. Our current studies are designed to: 1) elucidate the mechanism by which telomerase or telomere length regulate DNA MeTase activity and DNA methylation, 2) determine if there is a causal link between decreasing DNA MeTase activity and DNA methylation and cellular aging and 3) distinguish the changes in gene expression that occur during cellular aging and provide the trigger for cellular senescence from the myriad changes that occur as a result of p21 induction and growth arrest.


SELECTED PUBLICATIONS
1. Bertram, M.J., Berube, N.G., Hang-Swanson, X., Ran, Q., Leulng, J.K., Bryce, S., Spurgers, K., Baldini, A., Ning, Y., Clark, L.J., Parkinson, E.K., Barrett, J.C., Smith, J.R. and Pereira-Smith, O.M. Identification of a gene that reverses the immortal phenotype of a subset of cells and is a member of a novel family of transcription factor-like genes. Mol. Cell Biol. 19:1479-1485, 1999.

2. Morisaki, Hirobumi, Ando, Akikazu, Nagata, Yoshiho, Pereira-Smith, Olivia M., Smith, James R., Ideda, Kyoji, andNakanishi, Makoto. Complex Mechanisms Underlying Impaired Activation of Cdk4 and Cdk2 in Replicative Senescence: Roles of p16, p21, and Cyclin D1. Exp. Cell Res. 253:503-510, 1999.

3. Young, Juan, and Smith, James R. Epigentic aspects of cellular senescence. Exp. Geron. 35:23-32, 2000.

4. Katsanis, N., Venable, S., Smith, J.R., Lupski, J.R. Isolation of a Paralog of the Doyne Honeycomb Retinal Distrophy Gene from the Multiple Retinopathy Critical Region on 11q13. Hum Genet 106:66-72, 2000.

5. Ran, Q, Wadhwa, R, Kawai, R, Kaul, S.C., Sifers, R.N., Bick, R.J., Smith, J.R. and Pereira-Smith, O.M. Extramitochondrila localization of mortalin/mthsp70/PBP74/GRP75. Bichem. Biophys. Res. Comm. 275:174-179, 2000.

6. Thomas M, Popnikolov NK, Scott C, Smith JR, Hornsby PJ. Contrasting Roles of p57(KIP2) and p21(WAF1/CIP1/SDI1) in Transplanted Human and Bovine Adrenocortical Cells. Exp Cell Res. 2001 May 15;266(1):106-13.

7. Young JI, Smith JR. DNA Methyltransferase Inhibition in Normal Human Fibroblasts Induces a p21-dependent Cell Cycle Withdrawal. J Biol Chem. 2001 Jun 1;276(22):19610-6.

Updated on 06/20/2002