Abstract
The p16/pocket-protein pathway sets a balance between tumor suppression and capacity for tissue regeneration. Understanding the upstream signaling pathway that turns on the expression of p16 is required both for knowing the tumorigenic stresses from which this pathway provides protection and for appreciating the selective pressure that leads to the loss of this pathway in most human tumors. We report that COOH-terminal binding protein (CtBP), a physiologically regulated transcriptional corepressor that dimerizes to hold together repressive complexes, regulates p16 expression in primary human fibroblasts and keratinocytes. Interfering with CtBP-mediated repression increased p16 expression and accelerated senescence. CtBP had little influence on the expression of the alternate product of the CDKN2A tumor-suppressor gene, p14(ARF). Loss of CtBP-mediated repression diminished the Polycomb-based epigenetic histone mark that is reported to favor silencing of p16 via DNA methylation. Enhancing CtBP-mediated repression by growing cells in low oxygen increased the association of CtBP with the p16 promoter, as assessed by chromatin immunoprecipitation, and reduced p16 expression. Stresses and stimuli that reduce CtBP-mediated repression are associated with increased p16 expression; therefore, CtBP may provide a common final target for regulating the balance among tumor suppression, regenerative capacity, and senescence.
Highlights
The p16INK4A tumor suppressor protein (p16) inhibits the hyperphosphorylation of retinoblastoma-related pocket proteins that is required for cell cycle progression
We found that the adenoviral E1A and the SV40 large T oncoproteins differed substantially in the ability to increase p16 in human fibroblasts
Our findings—that COOH-terminal binding protein (CtBP) mediates the repression of p16, that loss of this repression resolves the epigenetic state of the p16 promoter into an activated form and increases p16 expression, and that ambient oxygen can affect p16 expression via CtBP—clarify several aspects of the regulation of this tumor suppressor
Summary
The p16INK4A tumor suppressor protein (p16) inhibits the hyperphosphorylation of retinoblastoma-related pocket proteins that is required for cell cycle progression. It prevents inappropriate division of stressed cells and can lead to permanent exit from the cell cycle via senescence [1, 2]. Mechanisms that couple signals to loss of epigenetic repression and to increased p16 expression, have not been identified. Few mechanisms that regulate p16 separately from the alternate product of the CDKN2A gene, p14ARF, are known
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