Normal human fibroblasts invariably undergo cellular senescence, whereby they irreversibly cease proliferation after a finite number of population doublings in culture. This number is inversely proportional to the age of the donor. Senescence in culture may be a manifestation, at the cellular level, of aging in vivo. It may also constitute an important mechanisms for surtailing tumorigenic progression. It is well-established that senescent human fibroblasts express one or more dominant inhibitor of cell proliferation. However, the nature of the irreversible growth arrest shown by senescent cells remains poorly understood. Recently, we identified several specific changes in gene expression that occur when human fibroblasts senesce. Senescent cells: 1) underexpress the mRNA for a non-cell cycle regulated gene of unknown function (pHE-7); 2) express a unique, polyadenylated histone variant mRNA; 3) show normal serum-dependent induction of two protoncogene mRNAs and ornithine decarboxylase (odc) mRNA, but are deficient in odc enzyme activity; 4) acquire a specific, transcriptional block that prevents the serum-dependent induction of the c-fos protooncogene. We propose to explore the mechanisms by which these changes in gene expression occur and to study their impact on cell proliferation. Specifically, we plan to: 1) clone and characterize the pHE-7 gene, examine the basis for its underexpression in senescent cells, and determine the effect of elevated expression on proliferation and senescence; 2) clone and characterize the histone variant expressed by senescent cells and identify factors that may be important in regulating expression in senescent cells; 3) continue our study of serum-inducible mRNAs, exploring the possibility that the expression of yet other genes may be altered at a transcriptional or posttranscriptional level in senescent cells; 4) identify factors that associate with regulatory regions in the c-fos gene and determine the impact of elevated fos expression on proliferation and senescence. These studies will provide a framework in which to begin to understand the molecular basis for cellular senescence and the irreversible block to cell proliferation.
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