p53-dependent apoptotic regulatory pathway (p53 pathway)

The p53-dependent apoptotic regulatory pathway is a fundamental tumor-suppressive network that orchestrates cellular responses to stress, primarily by inducing programmed cell death (apoptosis) to eliminate damaged or potentially malignant cells [6, 14]. Central to this pathway is the p53 protein, a transcription factor that, when activated by DNA damage or oncogenic signals, upregulates pro-apoptotic members of the Bcl-2 family, such as BAX, PUMA, and NOXA [4, 8]. Under normal conditions, the pathway is negatively regulated by MDM2, an E3 ubiquitin ligase that promotes p53 degradation [3, 7]. Mutations in the TP53 gene or overexpression of MDM2 are found in the majority of human cancers, leading to the evasion of apoptosis and therapeutic resistance [2, 5]. Pharmacological intervention strategies include the use of small-molecule MDM2 inhibitors to stabilize wild-type p53 and compounds like APR-246 that aim to restore the functional conformation of mutant p53 [9, 12]. Clinical development of these agents faces challenges such as on-target hematological toxicities and the emergence of resistance through secondary mutations [1, 5]. Additionally, the pathway's role extends to regulating cell cycle arrest, senescence, and metabolism, making it a master regulator of cellular fate [7, 15].

Other names

p53 signaling pathwayTP53-mediated apoptosisp53-dependent apoptosis pathwayp53-mediated apoptotic signaling pathway

MDM2 inhibition to stabilize wild-type p53; restoration of mutant p53 conformation; p53 gene replacement therapy; dual MDM2/MDMX inhibition.