Tumor suppressor p53 plays an important role in cancer prevention. Under normal conditions, p53 is maintained at a low level. However, in response to various cellular stresses, p53 is stabilized and activated, which, in turn, initiates DNA repair, cell‐cycle arrest, senescence and apoptosis. Post‐translational modifications of p53 including phosphorylation, ubiquitination, and acetylation at multiple sites are important to regulate its activation and subsequent transcriptional gene expression. Particularly, phosphorylation of p53 plays a critical role in modulating its activation to induce apoptosis in cancer cells. In this context, previous studies show that several serine/threonine kinases regulate p53 phosphorylation and downstream gene expression. The molecular basis by which p53 and its kinases induce apoptosis for cancer prevention has been extensively studied. However, the relationship between p53 phosphorylation and its kinases and how the activity of kinases is controlled are still largely unclear; hence, they need to be investigated. In this review, we discuss various roles for p53 phosphorylation and its responsible kinases to induce apoptosis and a new therapeutic approach in a broad range of cancers.

The tumor suppressor gene p53 regulates apoptosis in response to DNA damage. Promoter selectivity of p53 depends on mainly its phosphorylation. Particularly, the phosphorylation at serine-46 of p53 is indispensable in promoting pro-apoptotic genes that are, however, poorly determined. In the current study, we identified palmdelphin as a pro-apoptotic gene induced by p53 in a phosphorylated serine-46-specific manner. Upregulation of palmdelphin was observed in wild-type p53-transfected cells, but not in serine-46-mutated cells. Expression of palmdelphin was induced by p53 in response to DNA damage. In turn, palmdelphin induced apoptosis. Intriguingly, downregulation of palmdelphin resulted in necroptosis-like cell death via ATP depletion. Upon DNA damage, palmdelphin dominantly accumulated in the nucleus to induce apoptosis. These findings define palmdelphin as a target of serine-46-phosphorylated p53 that controls cell death in response to DNA damage.

Dual‐specificity tyrosine‐regulated kinases (DYRKs) are evolutionarily conserved from yeast to mammals. Accumulating studies have revealed that DYRKs have important roles in regulation of the cell cycle and survival. DYRK2, a member of the class II DYRK family protein, is a key regulator of p53, and phosphorylates it at Ser46 to induce apoptosis in response to DNA damage. Moreover, recent studies have uncovered that DYRK2 regulates G1/S transition, epithelial‐mesenchymal‐transition, and stemness in human cancer cells. DYRK2 also appears to have roles in tissue development in lower eukaryotes. Thus, the elucidation of mechanisms for DYRK2 during mammalian tissue development will promote the understanding of cell differentiation, tissue homeostasis, and congenital diseases as well as cancer. In this review, we discuss the roles of DYRK2 in tumor cells. Moreover, we focus on DYRK2‐dependent developmental mechanisms in several species including fly (Drosophila), worm (Caenorhabditis elegans), zebrafish (Danio rerio), and mammals.

Significance: The tumor suppressive function of p53 is tightly regulated by its posttranslational modifications. Although Ser46 phosphorylation is a critical modification for apoptosis induction, a molecular mechanism by which Ser46-phosphorylated p53 induces apoptosis remains unclear. Here, we clarify that amphiregulin (AREG) is specifically induced in a Ser46 phosphorylation-specific manner. Notably, AREG colocalizes with DEAD-box RNA helicase p68 (DDX5) in the nucleus and regulates tumor suppressive microRNA biogenesis in response to DNA damage. These findings support a model in which Ser46-phosphorylated p53 orchestrates tumor suppressive microRNA expression in the apoptotic response to DNA damage.