Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1

Abstract

The proliferation of mammalian cells is under strict control, and the cyclin-dependent-kinase inhibitory protein p27Kip1 is an essential participant in this regulation both in vitro and in vivo. Although mutations in p27Kip1 are rarely found in human tumours, reduced expression of the protein correlates well with poor survival among patients with breast or colorectal carcinomas, suggesting that disruption of the p27Kip1 regulatory mechanisms contributes to neoplasia. The abundance of p27Kip1 in the cell is determined either at or after translation, for example as a result of phosphorylation by cyclinE/Cdk2 complexes, degradation by the ubiquitin/proteasome pathway, sequestration by unknown Myc-inducible proteins, binding to cyclinD/Cdk4 complexes, or inactivation by the viral E1A oncoprotein. We have found that a mouse 38K protein (p38) encoded by the Jab1 gene interacts specifically with p27Kip1 and show here that overexpression of p38 in mammalian cells causes the translocation of p27Kip1 from the nucleus to the cytoplasm, decreasing the amount of p27Kip1 in the cell by accelerating its degradation. Ectopic expression of p38 in mouse fibroblasts partially overcomes p27Kip1-mediated arrest in the G1 phase of the cell cycle and markedly reduces their dependence on serum. Our findings indicate that p38 functions as a negative regulator of p27Kip1 by promoting its degradation.

Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions

“…12 Upon mitogenic stimulation, Jab1 causes p27 transfer to the cytoplasm and accelerates its degradation via the ubiquitin/proteasome pathway. 1,18,22 It has been shown that Jab1 has nuclear localization in proliferating cells, but cytoplasmic Jab1 increases as p27 relocates from nucleus to cytoplasm. 18,21 Recent studies revealed that Jab1 has both cytoplasmic and nuclear localization in undifferentiated tumors comparing with a predominantly nuclear localization in differentiated tumor cells.…”

“…1,18,22 It has been shown that Jab1 has nuclear localization in proliferating cells, but cytoplasmic Jab1 increases as p27 relocates from nucleus to cytoplasm. 18,21 Recent studies revealed that Jab1 has both cytoplasmic and nuclear localization in undifferentiated tumors comparing with a predominantly nuclear localization in differentiated tumor cells. 24,39 Significantly, in our series, we identified Jab1 cytoplasmic expression in 11 out of 36 (29%) p27-negative primary and metastatic melanoma cases.…”

“…[13][14][15][16] There are several possible mechanisms involved in cancer-associated abnormalities of p27 expression. 1,17,18 It has been shown that, although p27 protein is downregulated in human tumors, p27 mRNA is not, eliminating the possibility of transcriptional mechanisms as the cause of this decrease. 1 Also, mutations of the gene encoding p27 are rare, suggesting that alterations in mechanisms regulating its degradation are more likely to be involved.…”

“…1,17 It has recently been demonstrated that p27 degradation is accelerated by the c-Jun activation domain-binding protein-1 (Jab1). 18,19 Jab1 is a subunit of a large protein complex called COP9 signalosome, originally identified as a coactivator of the AP1 transcription factor, and involved in the control of cell proliferation. 20 Jab1 also causes translocation of p27 from the nucleus to cytoplasm, decreasing the p27 nuclear level and, thereby accelerating its degradation via the ubiquitinproteasome pathway.…”

Increase in p21 expression independent of the p53 pathway in bleomycin-induced lung fibrosis

“…Since p53 was mainly induced in the early phase, it is likely that p53 may have an important role in the initial phase that is when DNA were mainly damaged by bleomycin itself but not at a later stage when DNA are damaged mainly by infiltrating inflammatory cells.p21 is most probably playing an important role in the p53-induced G1 arrest because it is a potential inhibitor of cyclin-dependent kinase activity (Cheng et al, 1999;Haapajärvi et al, 1999;Rousseau et al, 1999;Sheikh et al, 1997;Tomoda et al, 1999;Wu et al, 1998a). It has been shown previously that serum or individual growth factors such as platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor but not insulin are able to induce p21 in quiescent p53-deficient cells as well as normal cells (Michieli et al, 1994).…”