Variations on a theme: Transcriptional regulation mediated through post-translational modification and microRNA function.

摘要

Mammalian cells use multiple mechanisms to alter cellular processes in order to adapt to ever-changing environmental conditions. Among these mechanisms, regulation of specific transcriptional targets is tightly controlled resulting in both short and long-term adaptation. Here, 1 present data concerning two alternate methods of transcriptional regulation. First, I show that PGC-1beta, a transcriptional coactivator involved in regulation of multiple metabolic processes, is acidulated by GCN5. Acetylation of PGC-1beta results in altered sub-cellular localization and a decrease in transcriptional coactivation potential. This transcriptional inhibition can be reversed through deacetylation by SIRT1, an NAD+-dependent deacetylase. Functionally, overexpression of PGC-1beta in skeletal muscle cells results in an increase in insulin-dependent glucose uptake which can be blocked by co-expression of GCN5. Second, I show that overexpression of the previously described HIF-1alpha-controlled hypoxamir miR-210 results in stabilization of the oxygen-dependent transcription factor HIF-1alpha and induction of HIF-1alpha transcriptional activity. I identify glycerol 3-phosphate dehydrogenase 1-like (GPD1L) as a novel target of miR-210 and knockdown of OPD1L phenocopies expression of miR-210, resulting in an increase in HIF-1alpha stability and transcriptional activity. Oppositely, overexpresion of GPD1L results in destabilization of HIF-1alpha and a concomitant increase in hydroxylation of HIF-1alpha a proline 564. I hypothesize that through regulation of GPD1L protein levels, miR-210 acts by a currently undetermined mechanism to suppress hydroxylation of HIF-1alpha, resulting in stabilization of this transcriptional activator. Together, these data show two different mechanisms by which cells regulate rates of transcription.