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Microinjection of Anti-p21 Antibodies Induces Senescent Hs68 Human Fibroblasts to Synthesize DNA but not To Divide¹

Cancer Center and Departments of Pharmacology and Medicine, University of California, San Diego, La Jolla, California 92093 [Y. M., S. A. P., T. L. B., J. R. F., B. L. B.]; Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093 [Y. M.]; Department of Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom [S. A. P.]; Immunex Corporation, Seattle, Washington 98101 [T. L. B.]; PharMingen, Inc., La Jolla, California 92121 [C. R. M.]; and The Scripps Research Institute, La Jolla, California 92037 [B. L. B.]

Replicative senescence is characterized by irreversible growth arrest and has been defined by four genetic complementation groups. One of these groups is associated with the predominance of underphosphorylated, growth-suppressive retinoblastoma tumor suppressor protein (pRb). Although certain members of the cyclin-dependent kinase (cdk)/cyclin family, some of which phosphorylate pRb, are underexpressed in senescent cells, others are expressed but inactive. This lack of cdk activity and arrest in the G₁ phase of the cell cycle is likely attributable to the induction upon senescence of the G₁-S cdk/cyclin inhibitors p21 (WAF1/CIP1/Sdi) and p16INK4. In fact, in early presenescent normal diploid fibroblasts in which p21 is inactivated, senescence is bypassed or postponed. Moreover, in senescent cells in which p53 function was inhibited, DNA synthesis was reinitiated, an effect likely attributable, in part, to the dependence of p21 expression on p53. We report here that the apparent inactivation of p21 in senescent human fibroblasts through the introduction of inhibitory -p21 antibodies causes these cells to reenter the S-phase of the cell cycle. The disruption of p21 activity affects the p21-Rb-E2F pathway in that the expression of genes transcriptionally regulated by E2F, such as cyclin A and cdc2, were found to be up-regulated in injected cells. No evidence of cell division was observed. This suggests that p21 plays an important role in the maintenance of senescence and in the inhibition of S-phase progression, but inhibition of p21 activity is insufficient to permit cells to complete the cell cycle.

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