Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence

Abstract

Alpha-2-macroglobulin (α2M), a protease inhibitor, is implicated in Alzheimer's disease, atherosclerosis, and other age-related diseases. The elevated level of α2M mRNA has been described in replicative senescence and it could be used as a biomarker of the aging cells. However, the mechanism responsible for the up-regulation of its expression is still unclear. This report identified a novel transcriptional regulatory element, the α2M transcription enhancement element (ATEE), within the α2M promoter. This element differentially activates α2M expression in senescent versus young fibroblasts. Electrophoretic mobility shift assays revealed abundant complexes in senescent cell nuclear extracts compared with young cell nuclear extracts. The DNase I footprint revealed the protein-binding core sequence through which the protein binds the ATEE. Mutation within ATEE selectively abolished α2M promoter activity in senescent (but not young) cells. These results indicated the ATEE, as a positive transcription regulatory element, contributes to the up-regulation of α2M during replicative senescence.

Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects

“…The findings from this previous study suggest that A2M regional regulatory elements may be involved in the regulation of alpha2M expression in a temporal or spatial manner (Li, et al, 2011). Both of the A2M SNPs analyzed in the present study are located within transcription factor ChIP sequence sites described by ENCODE, which further suggests that these SNPs may influence A2M gene expression (Rosenbloom, et al, 2010).…”

“…The promoter SNP (rs226379) analyzed in the present study is located near a previously described positive-transcription regulatory element that differentially regulates the A2M gene during replicative senescence (Li, et al, 2011). The findings from this previous study suggest that A2M regional regulatory elements may be involved in the regulation of alpha2M expression in a temporal or spatial manner (Li, et al, 2011).…”

Proper antiviral therapy for hepatitis B virus–associated acute-on-chronic liver failure

“…A number of growth factors bind to α 2 M at a site distinct from that where proteinases are entrapped, including members of transforming growth factor β (TGFβ) superfamily (Bowers et al, 2012). Some bind to native form of α 2 M, for example, carboxypeptidase A (Valnickova et al, 1996), some to both forms, for example, TGFβ2 (Li et al, 2011) and some only to transformed α 2 M, for example, growth hormone (GH; Fisker, 2006). The factors binding with native α 2 M remain stable in the circulation, while complexes of factors with transformed α 2 M are rapidly cleared from circulation via α 2 M‐receptors, hence, it is important to the physiology of the cytokine as to which form of α 2 M they are getting bound.…”