Syntaxin 6, a regulator of the protein trafficking machinery and a target of the p53 family, is required for cell adhesion and survival.

The p53 family consists of p53, p63, and p73. It has been well characterized that all of the p53 family proteins are transcription factors and capable of regulating cell cycle and apoptosis. To determine whether the p53 family exerts tumor suppression by other mechanisms, we set to identify novel p53 family target genes. Here, we found that the gene encoding STX6 (syntaxin 6), a vesicle transporter protein, is directly regulated by each of the p53 family proteins. In addition, STX6 can be induced by DNA damage and Mdm2 inhibitor Nutlin-3 in a p53-dependent manner. To examine how STX6 mediates the activity of the p53 family, STX6 is inducibly overexpressed or knocked down in various cell lines. We found that overexpression of STX6 alone has limited effect on cell proliferation. In contrast, we found that knockdown of STX6 inhibits cell proliferation and survival. We also found that knockdown of STX6 leads to cell cycle arrest and apoptosis. Interestingly, we found that p53 is necessary for STX6 knockdown-induced cell cycle arrest and apoptosis. Furthermore, we found that STX6 is necessary for proper expression of focal adhesion kinase and integrin alpha5 adhesion receptor. Consistent with this observation, STX6 knockdown inhibits cell adhesion. Together, we postulate that STX6 is an effector and a modulator of the p53 family in the regulation of cell adhesion and survival.