Dual regulation of telomerase activity through XXXX -dependent inhibition and alternative splicing of @entity2215 .

@entity1 @entity5 @entity517 @entity2533 @entity2215
Telomerase is believed to be induced upon proliferation and inhibited when cells differentiate. Thus, regulation of telomerase activity could be an important mechanism to limit growth of normal and @entity5 cells. Using @entity2533 ( @entity2533 ), which is known to control proliferation in epithelial cells, we now demonstrate that in the @entity1 HaCaT skin keratinocytes, @entity2533 downregulated @entity517 , and this blocked proliferation. This also caused a decrease in @entity2215 expression, which in turn inhibited telomerase activity. Overexpressing @entity2215 recovered telomerase activity but not proliferation, whereas constitutive expression of @entity517 recovered proliferation and @entity2215 expression. Nevertheless, telomerase remained inhibited, thus dissociating proliferation and telomerase activity. In addition, we show that @entity2533 inhibited telomerase activity despite ongoing @entity2215 transcription by inducing loss of the full-length @entity2215 transcript (mediating telomerase activity) and retaining high expression of the inactive beta variant. These changes in the splicing pattern reversed upon @entity2533 removal, as did inhibition of telomerase activity, suggesting that alternative splicing may represent a novel mechanism of telomerase regulation by @entity2533 . In addition, we show that destruction of tissue integrity (in a model for epidermal blistering) resulted in a rapid induction of the inactive beta variant, whereas tissue regeneration (formation of a stratified epithelium) correlated with a shift to the active full-length transcript, which is the dominant form in intact epidermis. Thus alternative splicing may not be restricted to @entity2533 but may add a more general mechanism of @entity2215 regulation in epidermal cells.
