Ser⁴⁶ phosphorylation of p53 is not always sufficient to induce apoptosis: Multiple mechanisms of regulation of p53-dependent apoptosis

The tumor suppressor gene p53 plays a central role in determining cell fate in response to DNA damage; cells may undergo either senescence or apoptosis, depending on cell type. Phosphorylation of Serine 46 (Ser⁴⁶) of p53 is considered to be a primary determinant for the induction of apoptosis, by selectively inducing transactivation of p53 target genes that have proapoptotic function. However, the generality of this mechanism of regulation of p53 remains a matter of debate. We investigated the role of p53 phosphorylation in adriamycin (ADR)-induced apoptosis. We found that Ser⁴⁶ was phosphorylated in four different cell lines undergoing ADR-induced senescence, as well as in two different cell lines undergoing ADR-induced apoptosis. Using alanine and glutamic acid substitution mutants of p53 Ser⁴⁶, we showed that Ser⁴⁶ phosphorylation is not a prerequisite for induction of the proapoptotic gene AIP1. These results indicate that Ser⁴⁶ phosphorylation of p53 is not required for ADR-induced apoptosis.