The Tumor Suppressor p53 Regulates c-Maf and Prox-1 to Control Lens Differentiation

L.      Zhang; D.      W.-C. Li; Y.      Liu; M.      -B. Yu; X.      -L. Liu; M.      -X. Wu; K.      Wu; J.      -P. Liu; S.      Sun; F.      -Y. Liu; J.      Liu; Z.      Woodward; L.      Gong; X.      Zhang; W.      Ji; P.      Chen; M.      Deng; X.      -C. Tang

doi:10.2174/156652412802480835

Abstract

The tumor suppressor p53 plays a key role in regulating apoptosis and cell cycle progression. In addition, p53 is implicated in control of cell differentiation in muscle, the circulatory system, ocular lens and various carcinoma tissues. However, the mechanisms by which p53 controls cell differentiation are not fully understood. Here we present evidence that p53 directly regulates c-Maf and Prox1, two important transcription factors controlling differentiation in the ocular lens. First, human and murine c-Maf and Prox1 gene promoters contain authentic p53 DNA binding sites. Second, p53 directly binds to the p53 binding sites found in the promoter regions. Third, exogenous p53 induces dose-dependent expression of the luciferase report gene driven by both c-Maf and Prox1 promoters, and p53 binds to both promoters in the ChIP assays. Fourth, in the in vitro differentiation model, knockdown of p53 significantly inhibits lens differentiation which is associated with downregulated expression of c-Maf and Prox1. Finally, in p53 knockout mice, the expression of c-Maf and Prox1 are significantly altered. Together, our results reveal that p53 regulates lens differentiation through modulation of two important transcription factors, c-Maf and Prox1, and through them p53 thus controls expression of various differentiation-related downstream crystallin genes.

Keywords: Lens, lens differentiation, cataract, p53, tumor suppressor, c-Maf, Prox-1, gene regulation, cell differentiation, transcription regulation, Bcl-2 family, cell cycle progression, erythrocytes, apoptosis, oncogenes.