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Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21WAF1/CIP1 mediated by STAT1

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The cell cycle is controlled by a family of CDKs, which can be negatively regulated by families of CDK inhibitors (1) such as p21 sup WAF1/CIP1/CAP1 (2, 3) An increase of the amount of p21 relative to the amount of cyclin-bound CDK may convert active CDK complexes into inactive ones (1, 4). Some of the genes that control the cell cycle are assumed to be regulated by cytokine-induced signals. Nevertheless, the molecular basis for such signaling in responses to cytokines is not well defined. A signaling pathway exists in which tyrosine kinases phosphorylate and activate STAT proteins containing a conserved Src homology 2 (SH2) domain (5, 6). The activated STAT proteins translocate from the cytoplasm to the nucleus (6, 7), and many immediate-early responsive genes are thought to be regulated by activated STAT proteins and their partner proteins (8).

EGF often stimulates cell proliferation, whereas IFNs usually inhibit cell proliferation. However, the growth of A431 cells, which are derived from epidermoid carcinomas, is inhibited by EGF (9). EGF, like IFNs, can induce tyrosine phosphorylation and activation of STAT proteins (10-12), especially in A431 cells. We therefore determined whether STAT activation by EOF correlated with suppression of cell growth. We used an electrophoretic mobility-shift assay (EMSA) to analyze many cell lines for STAT activation in response to EGF. STAT activation by EGF was very poor or absent in most cells except A431 cells (Fig. 1A) (13). (Figure 1 omitted) In contrast to A431 cells, in which STAT1 and STAT3 proteins were activated (represented by SIFs, or sis-induced factors, in Fig. 1A) (11) and cell growth was inhibited in response to EGF treatment (Fig. 1B), no detectable STAT activation was observed after EGF treatment of HT29 and WiDr cells (Fig. 1A) (13), which are derived from human colon adenocarcinomas. HT29 and WiDr cells...