Delineating functional mechanisms of the p53/p63/p73 family of transcription factors through identification of protein–protein interactions using interface mimicry

Abstract

Members of the p53 family of transcription factors-p53, p63, and p73-share a high degree of homology; however, members can be activated in response to different stimuli, perform distinct (sometimes opposing) roles and are expressed in different tissues. The level of complexity is increased further by the transcription of multiple isoforms of each homolog, which may interact or interfere with each other and can impact cellular outcome. Proteins perform their functions through interacting with other proteins (and/or with nucleic acids). Therefore, identification of the interactors of a protein and how they interact in 3D is essential to fully comprehend their roles.By utilizing an in silico protein-protein interaction prediction method-HMI-PREDwe predicted interaction partners of p53 family members and modeled 3D structures of these protein interaction complexes. This method recovered experimentally known interactions while identifying many novel candidate partners.We analyzed the similarities and differences observed among the interaction partners to elucidate distinct functions of p53 family members and provide examples of how this information may yield mechanistic insight to explain their overlapping versus distinct/opposing outcomes in certain contexts. While some interaction partners are common to p53, p63, and p73, the majority are unique to each member.Nevertheless, most of the enriched pathways associated with these partners are common to all members, indicating that the members target the same biological pathways but through unique mediators. p63 and p73 have more common enriched pathways compared to p53, supporting their similar developmental roles in different tissues.

The pathogenesis and development of targeted drugs in acute T lymphoblastic leukaemia

“…Almost most T‐acute lymphoblastic leukaemia patients have abnormal expression of cell cycle regulatory factors. Currently, the main cytokines discovered by university laboratories are cyclin‐dependent kinase inhibitor 2A (CDKN2A), cyclin‐dependent kinase 4 inhibitor B (CDKN2B) (Mai et al, 2016), tumor protein 73 (TP73) (Guven‐Maiorov et al, 2022) and DLX (distal‐less homeobox) (Zhou et al, 2016). In relapsed acute lymphoblastic leukaemia, gain‐of‐function mutations in the 5′‐nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6‐mercaptopurine (6‐MP).…”