Abstract
The cyclin-dependent kinase inhibitor p27KIP1 is a tumor suppressor gene in mice, and loss of p27 protein is a negative prognostic indicator in human cancers. Unlike other tumor suppressors, the p27 gene is rarely mutated in tumors. Therefore misregulation of p27, rather than loss of the gene, is responsible for tumor-associated decreases in p27 protein levels. We performed a functional genomic screen in p27+/− mice to identify genes that regulate p27 during lymphomagenesis. This study demonstrated that decreased p27 expression in tumors resulted from altered transcription of the p27 gene, and the retroviral tagging strategy enabled us to pinpoint relevant transcription factors. inhibitor of DNA binding 3 (Id3) was isolated and validated as a transcriptional repressor of p27. We further demonstrated that p27 was a downstream target of Id3 in src-family kinase Lck-driven thymic lymphomagenesis and that p27 was an essential regulator of Lck-dependent thymic maturation during normal T-cell development. Thus, we have identified and characterized transcriptional repression of p27 by Id3 as a new mechanism decreasing p27 protein in tumors.
Highlights
P27KIP1 binds to and thereby prevents cyclin-CDK complexes from phosphorylating their protein substrates [1]
We undertook a survey of the mouse genome to identify genes that modulate p27 protein levels in lymphomas
Our analysis discovered inhibitor of DNA binding 3 (Id3) as a negative regulator of p27 gene expression
Summary
P27KIP1 binds to and thereby prevents cyclin-CDK complexes from phosphorylating their protein substrates [1]. Analysis of p27À/À mice provides further evidence that p27 is an important regulator of cell proliferation in vivo. The quantity of p27 protein appears to mediate tumor susceptibility, and misregulation of p27 expression, rather than loss of its gene, is responsible for decreases in p27 protein levels. For this reason, if the pathways that cause p27 misregulation could be inhibited, the tumor suppressor function of p27 could potentially be restored in cancer cells.
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