Human smooth muscle α-actin gene is a transcriptional target of the p53 tumor suppressor protein

Abstract

Smooth muscle (sm) a-actin is expressed in vascular smooth muscle cells and ®broblast cells. Its expression is regulated by cell proliferation and repressed during oncogenic transformation. In this study, we demonstrate that p53 activation is associated with a dramatic increase in organized micro®lament bundles and an increase in sm a-actin mRNA level. Wild-type p53, but not mutant p53, strongly stimulated human sm a-actin promoter activity in p53 null cell lines. The sequences homologous to the p53 consensus sequence and to the p53 binding sequence from the muscle creatine kinase, were found within a speci®c region of the sm a-actin promoter. This sequence was su cient to confer p53-dependent activation to a heterologous promoter and p53 was capable of binding to this sequence as assessed by gel shift analysis. Ionizing irradiation of colorectal tumor cells caused an increase in a-actin mRNA level in a p53-dependent manner. Taken together, these results demonstrate that human sm aactin gene is a transcriptional target for p53 tumor suppressor protein and represents the ®rst example of a cytoskeletal gene with a functionally de®ned p53 response element.

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

“…α‐SMA is a direct transcriptional target of the tumor suppressor p53 and activation of a temperature sensitive p53 allele in rat embryo fibroblasts causes these cells to upregulate and express α‐SMA in actin filament bundles that resemble stress fibers of myofibroblasts (Comer et al, 1998). Since telomere dysfunction activates a p53 dependent DNA damage checkpoint (d’Adda di Fagagna et al, 2003; Herbig et al, 2004; Takai et al, 2003), it is possible that TGFβ1‐induced telomere dysfunction contributes to α‐SMA upregulation and transdifferentiation of myofibroblasts by promoting p53‐dependent α‐SMA expression.…”

Wild-type p53 protein shows calcium-dependent binding to F-actin

“…Sequentially activated gene transcript pro®les suggest that wildtype p53 down regulates g actin, tubulin and HSP70 gene expression (Madden et al, 1997) and Guenal et al (1997) have found that b and g actin genes are down-regulated during p53-mediated apoptosis. Others (Comer et al, 1998) have reported that p53 stimulates a-actin promoter activity, suggesting a role for p53 in cytoskeletal organization. At the protein level, indirect evidence for p53-actin interactions comes from the ®nding that actin ®lament disruption leads to p53 activation (Rubtsova et al, 1998).…”

Isolation and characterization of sixteen novel p53 response genes

“…In addition, it is noteworthy to list the proteins encoded by p53 regulated genes whose function is integral to the cytoskeletal architecture. This list includes actin (Comer et al, 1998), B99 a microtubule-localized protein (Utrera et al, 1998), the recently identi®ed p53 responsive caveolin-1 (Yu et al, 1999;Stahlhut and van Deurs, 2000), cytokeratins 8 (Mukhopadhyay and Roth, 1996) and 15 (this study), Ponsin/SH3 P12/ CAP (this study), and CDCrel2b/H5/PNUTL2 (this study). In support of this proposition Gloushankova et al (1997) reported that the disruption of actin bundles following mutant ras transformation of both ®bro-blasts and epitheliocytes was reversed by expression of wild type p53.…”