Ataxia-telangiectasia mutated-activated tumor protein p53-stratifin pathway (ATM-p53-SFN pathway)

The ATM-activated p53-14-3-3-sigma pathway is a critical signaling axis within the cellular DNA damage response (DDR) mechanism. Ataxia-telangiectasia mutated (ATM) kinase acts as the primary sensor for double-strand DNA breaks, initiating a cascade that leads to the activation and stabilization of the tumor suppressor protein p53 through direct phosphorylation and signaling via the intermediary kinase Chk2 [1, 11]. Once activated, p53 functions as a transcription factor to upregulate the expression of 14-3-3-sigma (also known as Stratifin or SFN), which promotes G2/M cell cycle arrest by sequestering the Cdc2-cyclin B1 complex in the cytoplasm, preventing premature entry into mitosis [6, 7]. This arrest allows the cell time to repair damaged DNA or, in cases of irreparable damage, triggers apoptosis to maintain genomic integrity [9]. Dysregulation of this pathway, frequently occurring through loss-of-function mutations in ATM or TP53, is a common driver of oncogenesis and resistance to radiotherapy and chemotherapy [10, 11]. Therapeutic strategies involve the use of ATM inhibitors (e.g., Peposertib) to sensitize tumor cells to DNA-damaging agents, and MDM2 inhibitors (e.g., Nutlin-3, Idasanutlin) to restore the p53-mediated response in tumors harboring wild-type p53 [5, 13, 15].

Other names

ATM-activated p53-14-3-3-sigma pathwayATM-p53-14-3-3σ signaling axisATM-p53-Stratifin pathwayp53-14-3-3σ axisATM-dependent p53 activation pathway

Drugs impacting this signaling axis primarily act through two mechanisms: the inhibition of Ataxia-telangiectasia mutated (ATM) kinase to block DNA double-strand break repair and sensitize cells to genotoxic stress, and the inhibition of the MDM2-p53 protein interaction to stabilize p53 and restore downstream transcriptional signaling through 14-3-3-sigma, leading to cell cycle arrest or apoptosis.