What remains one of the most fascinating areas in biological research is the mechanism regulating the events of aging. The main theme of this proposal suggests that a defined genetic program is in control of the irreversible termination of cell replication as cells become senescent. We have hypothesized that normal fibroblasts are destined for senescent nonproliferation as the initial part of a final program leading to death. Therefore senescence similar to terminal differentiation, may be a state, obligatory and dominant in every cell, and distinctly different from the transient growth-arrest seen in quiescence. Here we hypothesize that a specific program of gene expression sis activated for cells to become nonproliferative and senescent. The first step of our research along this line is to identify gene(s) or their product(s) uniquely present in senescent cells and absent in their young growing or nongrowing counterparts. We have succeeded in identifying a first example of such a gene product, terminin. Identification of terminin provides a handle to test our hypothesis by performing experiments to: (1) characterize terminin presence in tissues by immunohistochemical studies; (2) assess terminin expression qualitatively and quantitatively in tissues derived from young, middle-aged, and old animals; (3) characterize the cellular identity of terminin-positive granules by immunogold ultrastructural studies and histochemical enzymatic assays; (4) characterize possible biochemical mechanisms regulating terminin expression; (5) purify terminin polypeptides, sequence the protein and generate macromolecular probes; and (6) carry out initial cloning and sequencing of cDNA clones encoding for terminin proteins. Results of these experiments will provide us the necessary information and tools to investigate the next series of questions on how terminin gene expression is controlled and what is the function of the protein relating to the aging process. Ultimately, it will shed light on the mechanism of how cells turn off replication permanently as seen in fibroblasts senescence or terminal differentiation, the last part of a long physiological process preparing for the final event of apoptosis, the destiny of every cell.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG009278-02
Application #
3121095
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1990-09-01
Project End
1993-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Mcgill University
Department
Type
DUNS #
City
Montreal
State
PQ
Country
Canada
Zip Code
H3 0-G4
Marcotte, Richard; Qian, Jing-Fang; Chen, James et al. (2003) hMad4, c-Myc endogenous inhibitor, induces a replicative senescence-like state when overexpressed in human fibroblasts. J Cell Biochem 89:576-88
Semov, Alexandre; Marcotte, Richard; Semova, Natalie et al. (2002) Microarray analysis of E-box binding-related gene expression in young and replicatively senescent human fibroblasts. Anal Biochem 302:38-51
Wang, E; Marcotte, R; Petroulakis, E (1999) Signaling pathway for apoptosis: a racetrack for life or death. J Cell Biochem Suppl 32-33:95-102
Wang, E (1999) Age-dependent atrophy and microgravity travel: what do they have in common? FASEB J 13 Suppl:S167-74
Bernier, L; Wang, E (1996) A prospective view on phosphatases and replicative senescence. Exp Gerontol 31:13-9
Wang, E; Liu, D (1996) Characterization of senescence- and apoptosis-dependent forms of terminin as derived from a precursor found in replicating and nonreplicating cells. J Cell Biochem 60:107-20
Miller, M M; Teng, C J; Mitmaker, B et al. (1995) Characterization of the tissue regression process in the uterus of older mice as apoptotic by the presence of Tp30, an isoform of terminin. Eur J Histochem 39:91-100
Warner, H R; Fernandes, G; Wang, E (1995) A unifying hypothesis to explain the retardation of aging and tumorigenesis by caloric restriction. J Gerontol A Biol Sci Med Sci 50:B107-9
Wang, E; Pandey, S (1995) Down-regulation of statin, a nonproliferation-specific nuclear protein, and up-regulation of c-myc after initiation of programmed cell death in mouse fibroblasts. J Cell Physiol 163:155-63
Pandey, S; Wang, E (1995) Cells en route to apoptosis are characterized by the upregulation of c-fos, c-myc, c-jun, cdc2, and RB phosphorylation, resembling events of early cell-cycle traverse. J Cell Biochem 58:135-50

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