Inhibition of F-Box Protein p45SKP2Expression and Stabilization of Cyclin-Dependent Kinase Inhibitor p27KIP1in Vitamin D Analog-Treated Cancer Cells

Roberto Lin, Tian Tian Wang, Wilson H. Miller, John H. White
2003 Endocrinology  
Treatment of cancer cells with 1,25-dihydroxyvitamin D3 [1,25(OH) 2 D 3 ] or its analogs induces growth arrest and expression of the cyclin-dependent kinase inhibitor p27 KIP1 . Although 1,25(OH) 2 D 3 transiently enhances p27 kip1 gene transcription in some cells, its effects on p27 KIP1 protein levels are generally more gradual and sustained. This suggests that 1,25(OH) 2 D 3 treatment may be stabilizing p27 KIP1 protein, which is sensitive to modification by the SCF SKP2 protein ubiquitin
more » ... ase and proteosomal degradation. Here, we show that treatment of AT-84 head and neck squamous carcinoma cells with the 1,25(OH) 2 D 3 analog EB1089 increases p27 KIP1 protein levels without significantly affecting expression of its mRNA. EB1089 treatment repressed expression of mRNAs encoding the F-box protein p45 SKP2 , a marker of poor head and neck cancer prognosis, and the cyclin kinase subunit CKS1, which is essential for targeting p45 SKP2 to p27 KIP1 . This coincided with a reduction of total p45 SKP2 protein, and p45 SKP2 associated with p27 KIP1 . Consistent with these findings, turnover of p27 KIP1 protein was strongly inhibited in the presence of EB1089. A similar reduction in p45 SKP2 expression and stabilization of p27 KIP1 protein was observed in 1,25(OH) 2 D 3sensitive UF-1 promyelocytic leukemia cells, which also respond by transiently increasing p27 kip1 gene transcription. Our results reveal that 1,25(OH) 2 D 3 analogs increase levels of p27 KIP1 in different cell types by inhibiting expression of SCF SKP2 subunits and reducing turnover of p27 KIP1 protein. (Endocrinology 144: 749 -753, 2003)
doi:10.1210/en.2002-0026 pmid:12586749 fatcat:gt67bwtd3vabvktrbglflxnoli