Direct interaction with and activation of p53 by SMAR1 retards cell-cycle progression at G2/M phase and delays tumor growth in mice

The tumor-suppressor p53 is a multifunctional protein mainly responsible for maintaining genomic integrity. p53 induces its tumor-suppressor activity by either causing cell-cycle arrest (G(1)/S or G(2)/M) or inducing cells to undergo apoptosis. This function of wild-type p53 as guardian of the genome is presumably achieved by forming molecular complexes with different DNA targets as well as by interacting with a number of cellular proteins, e.g., Mdm2, Gadd45, p21, 14-3-3sigma, Bax and Apaf-1. Upon activation, p53 activates p21, which in turn controls the cell cycle by regulating G(1) or G(2) checkpoints. Here, we report SMARI as one such p53-interacting protein that is involved in delaying tumor progression in vivo as well as in regulating the cell cycle. SMARI is a newly identified MARBP involved in chromatin-mediated gene regulation. The SMARI gene encodes at least 2 alternatively spliced variants: SMARI(L) (the full-length form) and SMARI(S) (the shorter form). We report that expression of SMARI(S), but not of SMARI(L), mRNA was decreased in most of the human cell lines examined, suggesting selective silencing of SMARI(S). Overexpression of SMARI in mouse melanoma cells (BI6FI) and their subsequent injection in C57BL/6 mice delays tumor growth. Exogenous SMARI(S) causes significant retardation of BI6FI cells in the G2/M phase of the cell cycle compared to SMARI(L). SMARI(S) activates p53-mediated reporter gene expression in mouse melanoma cells, breast cancer cells (MCF-7) and p53 null cells (K562), followed by activation of its downstream effector, p21. We further demonstrate that SMARI physically interacts and colocalizes with p53. These data together suggest that SMARI is the only known MARBP that delays tumor progression via direct activation and interaction with tumor-suppressor p53. (C) 2002 Wiley-Liss, Inc.