Profile Details

Research Interest

Mechanisms of cellular immortalization
Role of telomeres and telomerase in cancer and aging
Cancer stem cells
hES and hiPS (normal stem cells)
Mouse models of radiation-induced cancer

Faculty Research Bio

In contrast to cancer cells, which have unlimited growth potential, normal cells display a limited capacity to divide and then undergo a growth arrest process called cellular senescence. Immortal cells, those with an unlimited life span, have escaped from normal senescence controls. Such an escape mechanism may also be one of the major changes leading normal human cells to become malignant tumors. Consequently, an understanding of the genes and mechanisms involved in cellular senescence and immortality would provide information about important steps in the development of cancer. We have shown that several genes originally discovered as tumor suppressors are involved in regulating cellular senescence. Our objective is to define the molecular basis of cellular senescence in human cells, with the long-term goal of applying this knowledge to the biology of cancer. We have proposed a two-stage model of cellular senescence and have obtained evidence that the cell cycle tumor suppressors p53 and Rb/p16 are part of the first mortality stage (M1). M1 is initiated when a few of the 92 telomere ends of human chromosomes become shortened and are recognized as DNA damage via cell cycle (or stress induced) check point arrest mechanisms. In the absence of these check points (e.g. p53 or p16/Rb), cells continue to divide until terminal telomere shortening initiates a second check point arrest (M2). We previously hypothesized and now have obtained experimental evidence that transfection of the catalytic subunit of telomerase results in telomerase expression and in escape from both M1 and M2. Thus, our present model is: 1) telomerase is a cellular reverse transcriptase that is silent in most somatic cells, compensates for the end-replication problem in germline and tumor cells, and is reactivated in somatic cells upon immortalization resulting in telomere stabilization, 2) in the absence of sufficient and functional telomerase activity, progressive telomere loss is the molecular measure (clock) regulating the onset of cellular senescence, 3) cellular senescence occurs when telomeres are short, and 4) telomerase or another means to maintain telomere length is a critical, perhaps rate-limiting, step in cancer progression. This telomere shortening mechanism may help protect long-lived organisms against the development of cancer in some instances and in other settings initiate genomic instability driving cancer progression. Specific goals of the laboratory are directed towards establishing molecular proofs for this model of aging and cancer by identifying, in addition to the telomerase template RNA component, the catalytic reverse transcriptase protein component, and p23/hsp90 chaperones, other components of the telomerase holoenzyme in order to investigate both the fundamental and applied aspects of this cellular reverse transcriptase. We are using the mTERT (telomerase) knockout mice to examine cancer in a humanized telomere length background. In addition, we seek to identify genes that specifically regulate the repression pathway of telomerase to more fully understand how these genes are altered in cancer progression. We believe the regulation of TERT splicing variants may be important in telomerase regulation. In addition, we are using genome wide shRNA approaches to investigate areas of telomerase assembly, recruitment to telomeres and processivity. We are also studying induced pluripotent stem cells and human embryonic stem cells to identify pathways regulating telomerase activation. Finally, we are testing novel reagents that inhibit telomerase activity to demonstrate that treatment of cancer cells will show progressive telomere shortening and then growth arrest (restore the cellular senescence program) or undergo apoptosis. At UTSW there are now two early stage clinical trials utilizing a telomerase inhibitor (GRN163L) in patients with advanced lung cancer and CLL and one immunotherapy trial targeting telomerase in AML.

Address

UT Southwestern Medical Center at Dallas
5323 Harry Hines Blvd
Dallas, Texas 75390

Contact:

214-648-3282

Recent Publications

Jackson, S.R, Zhu, C-H., Paulson,V., Watkin, L., Dikemen, Z.G., Gryaznov, S.M., Wright, W.E. and Shay, J.W. , " Anti-adhesive effects of GRN163L: an oligonucleotide, N3-P5 thio-phosphoramidate targeting telomerase. "Cancer Research ,67:1121-1129 ,Spring 2007

Tsakiri, K.D., Cronkite, J.T., Kuan, P.J. Xing, C., Ganesh, R., Weissler, J.C., Rosenblatt, R.L. Shay, J.W. Garcia, C.K , " Adult-onset pulmonary fibrosis caused by mutations in telomerase "PNAS ,104:7552-7557 ,Spring 2007

Pearce, V.P. ... Shay, J.W. , " Resveratrol facilitates immortalization of epithelial prgenitor cells "Oncogene ,27:2365-2374 ,Spring 2008

Roig, A. I. , Hight, S.K., and Shay, J.W. , " Two and three dimensional models for risk assessment of radiation-enhanced colorectal turmorigenesis "Radiation Research ,in press,Fall 2008

Y-S Cong, J.W. Shay , " Actions of human telomerase beyond telomeres "Cell Research ,18:725-732 ,Spring 2008

Significant Publications

Morales, C.P., Holt, S.E., Ouelette, M., Kaur, K.J., Wilson, K.S., White, M.A., Wright, W.E., and Shay, J.W, , " Lack of cancer-associated changes in human fibroblasts after immortalization with telomerase. "Nature Genetics ,21:115-118 ,1999

Hiyama, E., Hiyama, K., Yokoyama, T., Matsuura, Y., Piatyszek, M.A., Shay, J.W. , " Correlating telomerase activity levels with human neuroblastoma outcomes. "Nature Medicine ,1:249-357 ,1995

Baur, J.A., Shay, J.W. and Wright, W.E. , " Telomere position effect in human cells. "Science ,292:2075-2077 ,2001

Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West, M.D., Ho, P.L.C., Coviello, G.M., Wright, W.E., Weinrich, S.L., Shay, J.W. , " Specific association of human telomerase activity with immortal cells and cancer. "Science ,266:2011-2015 ,1994

Bodnar, A.G., Ouellete, M., Frolkis, M., Holt, S.E., Chiu, C.P., Morin, G.B., Harley, C.B., Shay, J.W., Lichtsteiner, S., and Wright, W.E. , " Extension of lifespan by introduction of telomerase in normal human cells. "Science ,279:349-352 ,1998