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The second and third most frequently mutated genes are PIK3CA that encodes the p110 alpha catalytic subunit of PI3 kinase and PTEN, a lipid phosphatase that regulates Akt kinase activation, which are mutated in 17.8 and 9.7% of the cases of the 12 common tumor types, respectively ( Wild type p53 protein induces cell cycle arrest, senescence, and apoptosis in response to cellular stress by upregulating target genes such as p21, Bax, Puma, and Noxa ( In vivo studies in mice have shown that certain engineered p53 mutants that fail to transactivate pro-arrest and pro-apoptosis target genes can still prevent tumor development ( Oncogenic stress as a result of oncogene activation or loss of cell cycle control characterizes early stages of tumor evolution

ROS-induced AP-1 prevents the TGF-/Smad signal pathway in fibroblasts that control collagen synthesis to prevent a decrease in collagen production (76)