Binding of ΔNp63 to the promoter of p21, a p53‐dependent cell cycle arrest gene, modifies the response of salivary glands to therapeutic radiation

Abstract

Radiotherapy targeting head and neck tumors often results in persistent loss of function in the salivary glands, leading to severe malnutrition other debilitating side effects in these patients. Radiation‐induced salivary gland damage results from attrition of salivary cells to p53‐dependent apoptosis. In p53 knockout mice as well as in mice expressing a constitutively active form of Akt (myr‐Akt1), this apoptosis is suppressed, and slaivary gland function is maintained. Injections of IGF1, a potent activator of Akt in salivary glands, also results in preservation of irradiated glands. Induction of cell cycle arrest may be important for this protection by allowing cells time for extensive DNA repair. We have observed increased accumulation of cells in G2/M and a reduction in proliferation at acute time‐points following irradiation in salivary glands of mice receiving pre‐treatment with IGF1. IGF1 also leads to a decreased stress response in irradiated glands as indicated by reduced stress‐induced phosphorylation of p53 (Ser18) and ΔNp63 (Ser160/162). The ΔN isoforms of p63 are thought to act as dominant negatives to p53‐induced gene expression. Given that several p53 target genes, including p21, are involved in cell cycle regulation, this suggests a mechanism by which IGF1’s affects on p63 could modulate arrest. Interestingly, pre‐treatment with IGF1 reduces binding of ΔN to the p21 promoter following irradiation, which may allow p53 to transactivate that gene and initiate arrest and repair, resulting in long‐term preservation of salivary gland function. Support: NIDCR K22 (DE16096), CBIO T32 (CA09213), NSF GK‐12 (0338247).