Regulation of Cell Migration by the Tumor Suppressor p53.

摘要

The tumor suppressor p53 is a transcription factor that regulates the expression of multiple target genes. These targets, in turn, effect DNA repair, apoptosis, or cell cycle arrest in response to p53 activity. p53 is found to be mutated in over half of human cancers. Many aggressive forms of cancer, however, retain wild-type p53. This fact leads to the possibility that retention of functional wild-type p53 may be beneficial to tumor progression in some contexts. Indeed, the presence of wtp53 has promoted cancer cell survival and chemoresistance in multiple cancer types. Whether p53 plays a advantageous role in other events during cancer progression and metastasis, such as migration, remains understudied.;Slug/SNAI2, a zinc-finger transcription factor, is deregulated in multiple cancer types and has been shown to enhance cell migration during development, wound healing, and in cancer progression. Induction of wild-type p53 in response to doxorubicin, nutlin-3, or by ectopic expression, resulted in p53-dependent up-regulation of Slug protein and mRNA. p53 was found to regulate Slug through direct binding to the SNAI2 gene. p53-dependent elevation of Slug expression was also found to enhance cell migration in human cancer cell lines. Additionally, transcription levels of two other pro-migratory proteins, Myosin Light Chain Kinase (Mlck) and Rac2, were increased in response to p53 activation. The ability of wtp53 to induce cell migration could be co-opted by cancer cells, lending one possible advantage of its retention.;While p53 is found to enhance migration through the induction of Slug, p53 is also found to repress many other pro-migratory factors. EpCAM, a molecule highly expressed in multiple cancers, was found to be down-regulated by p53 in response to ectopic expression or nutlin treatment. Additionally, Zeb1 and Snail were repressed in response to p53 increase. Furthermore, the repression of Snail was also achieved by p21, indicating p53 mediated repression of Snail may be indirect. Finally, Twist repression was also observed by p53, however this was largely dependent on cell confluence, as increasing confluence alone reduced Twist expression levels. The work presented below outlines the role of wild type p53 in the regulation of cell migration. While p53 is found to enhance cell migration, it does this specifically through Slug expression while simultaneously repressing Snail, Zeb1, EpCAM, and Twist. The novel capability of wild-type p53 to induce motility may be another mechanism by which p53 is able protect a cell from DNA damage, this context by escaping a toxic environment, ultimately deciding between migration or apoptosis.