Normal mammalian cells have a finite capacity for division in culture. After completing their in vitro lifespan they enter a non-dividing state that has been termed cellular senescence. This phenomenon has been most extensively studied in normal human diploid fibroblasts. A number of changes in gene expression have been observed when cells become senescent. However, it has not been possible to determine which changes are the cause as distinct from the result of cellular senescence. Cell fusion studies have clearly demonstrated that the senescent phenotype is dominant and that immortal cells result from recessive changes in the normal cell program. Evidence has accumulated over the past several years that senescent cells produce an inhibitor(s) of DNA synthesis. One such DNA synthesis inhibitor (SDI-1) was cloned from a senescent cell cDNA library, and was the first of a group of Cdk inhibitors to be discovered. Subsequently, six Cdk inhibitors have been cloned, many of which can inhibit DNA synthesis when over-expressed in mammalian cells. The mRNA level of Sdi1 (p21) is over-expressed 10-20 fold in senescent compared with young human diploid fibroblasts. We have found that decreasing the level of p21, following induction of antisense p21 sequences, results in stimulation of density inhibited, young human fibroblasts to undergo DNA synthesis and divide. However, expression of antisense p21 in senescent human cells is not sufficient to cause them to enter S phase. Therefore, we hypothesize that the inability of senescent cells to synthesize DNA may be due to the over-expression of multiple Cdk inhibitors, and the goal of this project is to determine the role of Cdk inhibitors in cellular senescence.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
United States
Zip Code
Young, Juan I; Sedivy, John M; Smith, James R (2003) Telomerase expression in normal human fibroblasts stabilizes DNA 5-methylcytosine transferase I. J Biol Chem 278:19904-8
Thomas, Michael; Suwa, Tetsuya; Yang, Lianqing et al. (2002) Cooperation of hTERT, SV40 T antigen and oncogenic Ras in tumorigenesis: a cell transplantation model using bovine adrenocortical cells. Neoplasia 4:493-500
Zhang, Hao; Hornsby, Peter J (2002) Intradermal cell transplantation in soluble collagen. Cell Transplant 11:139-45
Hornsby, Peter J (2002) Aging of the human adrenal cortex. Ageing Res Rev 1:229-42
Tominaga, Kaoru; Pereira-Smith, Olivia M (2002) The genomic organization, promoter position and expression profile of the mouse MRG15 gene. Gene 294:215-24
Pardo, Patricia S; Leung, James K; Lucchesi, John C et al. (2002) MRG15, a novel chromodomain protein, is present in two distinct multiprotein complexes involved in transcriptional activation. J Biol Chem 277:50860-6
Hornsby, Peter J; Yang, Lianqing; Thomas, Michael (2002) Adrenocortical cell proliferation in a cell transplantation model: the role of SV40 T antigen. Endocr Res 28:777-83
Hornsby, Peter J (2002) Cellular senescence and tissue aging in vivo. J Gerontol A Biol Sci Med Sci 57:B251-6
Thomas, Michael; Wang, Xiangdong; Hornsby, Peter J (2002) Human adrenocortical cell xenotransplantation: model of cotransplantation of human adrenocortical cells and 3T3 cells in scid mice to form vascularized functional tissue and prevent adrenal insufficiency. Xenotransplantation 9:58-67
Tominaga, Kaoru; Olgun, Abdullah; Smith, James R et al. (2002) Genetics of cellular senescence. Mech Ageing Dev 123:927-36

Showing the most recent 10 out of 47 publications