Altered Expression of the CIP/KIP Family CDK Inhibitors in Tumor Phenotype-Suppressed Human Lung Cancer Cells

Abstract

The cyclin-dependent kinase inhibitor (CDKI) plays pivotal roles in the control of mammalian cell cycle progression as well as in tumor suppression. However, there is relatively few evidences describing an involvement of these inhibitors in the suppression of tumor development in humans. Here we focused on the Cip/Kip family CDK inhibitors, and investigated their roles in the tumor suppressive phenotypes observed in human lung cancer-derived cells. We unexpectedly found that p21^Wafl/Cipl protein level was decreased concomitant with tumor suppression, although mRNA level of p21 ^Wafl/Cipl was conversely up-regulated. Observed transcriptional activation of p21 ^Wafl/Cipl was partly attributable to increased p53 activity. These data imply that post-transcriptional p21^Wafl/Cipl down-regulatory mechanism is activated in the tumor phenotype-suppressed lung cancer cells. We also found that serum starvation-triggered p27^Kipl induction pathway is exclusively up-regulated concomitant with tumor suppression, whereas cell contact- or TGF-β-responsible p27^Kipl induction pathway was unaffected. These data suggest that restriction point control-associated p27^Kipl induction is an important pathway for tumor suppression, and that frequently observed p27^Kipl down-regulation in human tumors might be attributable to inactivation of this mitogen starvation-responsible pathway.