What is it about?
p73, unlike its tumor-suppressor family member p53, is not mutated in cancers. TAp73 exhibits both growth inhibitory and promoting properties, though the mechanistic basis for differential regulation is unclear. We identified an alternate functional region in TAp73β at the C-terminus, which is required for selective activation of targets involved in growth and migration, and mediates FAK activation. This is distinct from the currently known functional region at the N-terminus, similar to that found in p53, and which activates growth-inhibitory targets. DNAJA1, identified as a TAp73β C-terminal binding partner, selectively participates in the activation of targets involved in promoting cellular growth and migration. These data together provide important insights into the mechanistic basis for TAp73’s dual role.
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Why is it important?
As a homolog of the p53 family genes, TAp73 was collectively believed to be as a tumor suppressor alike p53. However, it is also frequently found to be overexpressed in cancers instead of being mutated, raising the controversy on its real role in tumorigenesis. Results from mouse models also exhibit conflicting phenotypes reported by different research laboratories, and thus it is of significance for scientific and biomedical researches to resolve these inconsistencies. The findings from this paper identified a previously unknown functional domain on top of the one resembling to p53, demonstrating that TAp73 has evolved to have two different functional units to promote or inhibit cell growth and motility in context-dependent manner. These results not only provide a possible explanation to the controversy on TAp73 function, and also highlight the complexity of gene regulation of p53 family members.
Perspectives
The cancer research field, p53 has played indispensable roles since it's discovered decades ago. TAp73, as a homolog of p53, has also been extensively investigated. However, its exact role in tumor development remains elusive. Some papers reported it functions as a tumor suppressor, while others as tumor promoter. Addressing this controversy was a great pleasure as our results published here provide an convincing answer to this question both at molecular and cellular levels as well. However, more questions are raised before completely solving this puzzle. In the future, it will be much more interesting and significant to know what is extracellular signals/stimuli which distinctly trigger these two dependent and also independent functional unit to coordinate cell growth and migration during tumor development.
Dan Li
Nanyang Technological University
Read the Original
This page is a summary of: Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73, Proceedings of the National Academy of Sciences, May 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2318591121.
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