During attempts to isolate the inhibitor of DNA synthesis produced by senescent cells, we have discovered that fibronectin (fn) production by senescent cells is quantitatively and qualitatively different from young cells. The major goal of this project is to determine the role of changes in fn in cellular senescence. These changes could be directly responsible for the loss of proliferative potential that occurs at senescence. Alternatively, they could be part of a pleiotropic response to changes in gene expression that occur with cellular senescence, and as such provide a prototype gene with which to investigate the mechanisms of altered gene expression during in vitro aging. To achieve this goal, we will determine if the fn produced by senescent cells is structurally different from that produced by young cells, by studying splicing variations in the fn mRNA and postranslational modification of the fn protein. We will determine the response of the endogenous fn gene to a variety of cell types as they age in culture. We will determine the response of the endogenous fn gene to a variety of agents. This will be complementary to experiments with fn promoter-CAT constructs. We will determine whether other genes that are up-regulated in senescence are regulated in a manner similar to fn. To investigate the functional significance of fn changes seen with senescence, we will modulate the expression of fn in young and senescent cells and determine the effect on DNA synthesis. We will add fn extracted from senescent and young cells and human plasma to young and senescent cells to determine the effect on cell proliferation. The significance of the presence of particular epitopes of fn on senescent cells will be investigated by determining whether senescent cells can bind the fn fragment on which the epitope is located.

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
Duttaroy, A; Qian, J F; Smith, J S et al. (1997) Up-regulated P21CIP1 expression is part of the regulation quantitatively controlling serum deprivation-induced apoptosis. J Cell Biochem 64:434-46
Smith, J R; Nakanishi, M; Robetorye, R S et al. (1996) Studies demonstrating the complexity of regulation and action of the growth inhibitory gene SDI1. Exp Gerontol 31:327-35
Yang, L; Didenko, V V; Noda, A et al. (1995) Increased expression of p21Sdi1 in adrenocortical cells when they are placed in culture. Exp Cell Res 221:126-31
Kaul, S C; Wadhwa, R; Matsuda, Y et al. (1995) Mouse and human chromosomal assignments of mortalin, a novel member of the murine hsp70 family of proteins. FEBS Lett 361:269-72
Wadhwa, R; Pereira-Smith, O M; Reddel, R R et al. (1995) Correlation between complementation group for immortality and the cellular distribution of mortalin. Exp Cell Res 216:101-6
Nakanishi, M; Robetorye, R S; Pereira-Smith, O M et al. (1995) The C-terminal region of p21SDI1/WAF1/CIP1 is involved in proliferating cell nuclear antigen binding but does not appear to be required for growth inhibition. J Biol Chem 270:17060-3
Hensler, P J; Pereira-Smith, O M (1995) Human replicative senescence. A molecular study. Am J Pathol 147:1-8
Khaoustov, V I; Ozer, A; Smith, J R et al. (1995) Induction of senescent cell-derived inhibitor of DNA synthesis gene, SDI1, in hepatoblastoma (HepG2) cells arrested in the G2-phase of the cell cycle by 9-nitrocamptothecin. Lab Invest 73:118-27
Nakanishi, M; Robetorye, R S; Adami, G R et al. (1995) Identification of the active region of the DNA synthesis inhibitory gene p21Sdi1/CIP1/WAF1. EMBO J 14:555-63
Aggarwal, B B; Totpal, K; LaPushin, R et al. (1995) Diminished responsiveness of senescent normal human fibroblasts to TNF-dependent proliferation and interleukin production is not due to its effect on the receptors or on the activation of a nuclear factor NF-kappa B. Exp Cell Res 218:381-8

Showing the most recent 10 out of 39 publications