MicroRegulators come of age in senescence

Cells progressing to senescence acquire several prominent phenotypes and the levels of many proteins governing each of these phenotypes are influenced by senescence-associated miRNAs. As shown in the light gray boxes, senescent cells have elevated levels of p53 (subject to negative regulation by MCM5, a protein repressed by miR-885-5p), which transcriptionally upregulates miR-34 expression; in turn, miR-34 represses the levels of several proliferative proteins (E2F, c-Myc, cyclins and cdks) and anti-apoptotic proteins (Bcl-2, SIRT1). Senescent cells also have active (hypophosphorylated) RB, resulting from elevated levels of two potent inhibitors of cdks (the RB kinases), p21 (upregulated in part via p53) and p16; a number of miRNAs that reduce p21 and p16 abundance have been reported. Senescence cell-specific gene expression programs are controlled via changes in proteins that modulate gene transcription (via promoter elements or chromatin remodeling) like Bmi-1, HMGA2, RARγ, and B-Myb, and proteins that affect gene expression post-transcriptionally like the splicing factor ASF/SF2 and the mRNA-stabilizer and translation regulator HuR; each of these proteins is also subject to control by senescence-associated miRNAs and some of them in turn cross-talk with the p53/p21 pathway (HMGA2 represses p21 transcription) and with the p16/RB pathway (Bmi-1 represses p16 transcription). Importantly, not only are we learning how miRNAs affect senescence, but we are also discovering how senescence factors directly modulate the expression of miRNAs; for example, p53 transcriptionally upregulates miR-34 and RB transcriptionally upregulates miR-29/miR-30. In addition, senescent cells also secrete a distinctive subset of proteins, a feature known as SASP; secretion of some of these factors (e.g., IL-6 and IL-8) is under control of IRAK1, a protein whose levels are reduced by the senescence-associated miR-146. Factors secreted through the SASP, as well as lower integrin β1 activity resulting from higher miR-183 affect ECM function.These pathways and regulatory processes influence key aspects of the senescence phenotype (dark gray). Major downstream consequences of activation of p53/p21 and p16/RB and gene regulatory factors are the inhibition of the cell division machinery and the implementation of senescence-associated gene expression patterns. The p53/p21 and p16/RB pathways elicit cell responses to cell damage by genotoxins and oxidants. The main consequences of the SASP are the secretion of factors that cause inflammation and compromise the integrity of the ECM.

Publication

MicroRegulators come of age in senescence. () Myriam Gorospe, et al. Trends Genet. ;27(6):233-241. Figure: F1. All organisms Danio rerio Homo sapiens

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