p53 Activation in Genetic Disorders: Different Routes to the Same Destination

Abstract

The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.

The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia

“…Abnormal p53 activation has been observed in several congenital syndromes, such as Diamond-Blackfan anemia and Fanconi anemia, that are caused by mutations in ribosome biogenesis or DNA repair pathways. Mouse models of these disorders in general can recapitulate human traits, and disorder-related phenotypes can be alleviated by inactivation of p53 ( Bowen and Attardi, 2019 ; Tsai et al., 2021 ). Therefore, our present result indicated that TAR syndrome belongs to a p53-activation-associated genetic disorder.…”

Dynamics and structural changes of calmodulin upon interaction with the antagonist calmidazolium

“…Such CaM inhibitors might find broad medical applications, as illustrated by Taylor and colleagues [ 68 ], who provided evidence that CaM inhibitors could be efficacious in rescuing a genetic disease (Diamond-Blackfan anemia, DBA) that results from increased expression of tumor suppressor protein 53. This study suggests that CaM inhibition may offer a potential therapeutic path for treatment of DBA and other diseases characterized by aberrant p53 activity [ 68 , 69 ].…”

Identification of 3-Phenylquinoline Derivative PQ1 as an Antagonist of p53 Transcriptional Activity

“… 8 Although antagonists of p53 transcriptional activity provide prospective therapeutic applications, p53 inhibitors have not been applied in clinic. 29 Thus, discovering small-molecule inhibitors of p53 is an important research goal for generating drug leads of therapeutic strategies targeting p53 function. Our research provides a new choice for exploring the clinical significance of inhibiting p53 function.…”

“…NSC194598 protects mice from radiation toxicity via inhibiting transcriptional output . Although antagonists of p53 transcriptional activity provide prospective therapeutic applications, p53 inhibitors have not been applied in clinic . Thus, discovering small-molecule inhibitors of p53 is an important research goal for generating drug leads of therapeutic strategies targeting p53 function.…”