The occurrence of oncogenic events in cancer cells such as loss of tumor suppressors (p53, TSC1, TSC2, and PTEN) [98–100] and activation or overexpression of oncogenic pathways (HRAS, BRAF, and RET) [95, 101, 102] exacerbates ER stress by increasing the overall rates of protein translation which result in nutrient deprivation, acidosis and hypoxia, as well as challenging the protein folding capacity leading to ER stress [71, 95, 103, 104] (Fig. 2). The gene discussed is TP53; the disease is cancer.