Senescent cells fail to express cdc2, cycA, and cycB in response to mitogen stimulation.

Abstract

Senescent human diploid fibroblasts (HDF) (2), which identified the human homologue of cdc2, showed that the human cdc2 gene can supply the G1/S and G2/M functions of S. pombe cdc2 in mutants of that organism. Finally, Lee et al. (8) have shown that the increase in cdc2 RNA and protein narrowly precedes the increase in DNA synthesis in serum-stimulated quiescent human diploid fibroblasts (HDF). On the other hand, there are reports that injection of rat fibroblasts with antisera to p34`1`did not block entry into S phase (9) and that mouse cells with a temperature defect in p34cdc2 arrested in G2 but not in G' at the nonpermissive temperature (10); however, both studies discuss the possibility that a G1/S function of p34CdC2 was not affected in these experiments.Cell proliferation in HDF is regulated at three levels: passage through the mitotic cycle, entry into and exit from quiescence, and cessation of proliferation owing to cellular senescence. In senescence and quiescence, the cells are rrested with G1 phase DNA contents and can be maintained in the nonreplicative state for many months (11,12). When serum stimulated, senescent HDF express many of the same cell-cycle-regulated genes as do serum-stimulated quiescent HDF-e.g., expression of c-myc, c-jun, and c-Ha-ras (13-15). However, in contrast to serum-stimulated quiescent HDF, serum-stimulated senescent HDF fail to express c-fas (15) 11012The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Tumor suppression without differentiation or apoptosis by antisense cyclin D1 gene transfer in K1735 melanoma involves induction of p53, p21WAF1 and superoxide dismutases

“…These properties were paralleled by a relative increase in the non-phosphorylated tumor suppressive form of Rb, 22 and by an increased binding of the cdk inhibitor p27 KIP1 to cyclin A and cdk2, 28 properties known to be associated with growth arrest, since they decrease the ability of cells to enter S-phase. 28 Although senescent normal fibroblasts do not express cyclin A, 30 a number of tumor cells fail to down-regulate cyclin A with serum starvation 31,32 or terminal differentiation, 33 even those transduced with antisense to cyclin D1 (Figure 3). However, the aberrantly regulated cyclin A pathway of malignant cells 31 ± 33 can be bypassed in the latter cells by suppressing tumor growth through down-regulation of cyclin D1.…”

Bcl-2 activates a programme of premature senescence in human carcinoma cells

“…flat and enlarged morphology (Figures 1, 3 and 8), cytoplasmic vacuolization (Figure 1), expression of SA-β-gal (Figures 1 and 3) and inhibition of proliferation (Figure 2). In addition, senescent cells typically demonstrate increased expression of cyclin-dependent kinase inhibitors and downregulation of E2F-regulated genes [40], both features displayed by H1299 cells expressing Bcl-2 over a long period.…”

Senescence from G2 arrest, revisited

“…pRb phosphorylation, 40 together with the presence of G1 cyclins (cyclins D1 and E1) 27 and the lack of mitotic cyclins (cyclin B1), 41 is an early-recognized hallmark of senescence. Very soon after its discovery, p16 Ink4a (p16), another pRb regulator that specifically inhibits the cyclin D1-associated kinases Cdk4 and Cdk6, was also implicated in senescence 28,[42][43][44] (Fig.…”