Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73

• 成果类型: Article
• 署名作者: Li, Dan; Kok, Catherine Yen Li; Wang, Chao; Ray, Debleena; Osterburg, Susanne; Doetsch, Volker; Ghosh, Sujoy; Sabapathy, Kanaga
• 署名单位: National Cancer Centre Singapore (NCCS); National University of Singapore; Goethe University Frankfurt; Goethe University Frankfurt; Goethe University Frankfurt; National University of Singapore; National University of Singapore; Nanyang Technological University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14428
• DOI: 10.1073/pnas.2318591121
• 发表日期: 2024-05-21
• 关键词: focal adhesion kinase; p73 gene; apoptotic response; signaling pathways; terminal region; dna-binding; p53; expression; overexpression; protein

摘要

The transcription factor p73, a member of the p53 tumor - suppressor family, regulates cell death and also supports tumorigenesis, although the mechanistic basis for the dichotomous functions is poorly understood. We report here the identification of an alternate transactivation domain (TAD) located at the extreme carboxyl (C) terminus of TAp73 (3 , a commonly expressed p73 isoform. Mutational disruption of this TAD significantly reduced TAp73 (3 's transactivation activity, to a level observed when the amino (N) - TAD that is similar to p53's TAD, is mutated. Mutation of both TADs almost completely abolished TAp73 (3 's transactivation activity. Expression profiling highlighted a unique set of targets involved in extracellular matrix-receptor interaction and focal adhesion regulated by the C - TAD, resulting in FAK phosphorylation, distinct from the N - TAD targets that are common to p53 and are involved in growth inhibition. Interestingly, the C - TAD targets are also regulated by the oncogenic, amino - terminal - deficient DNp73 (3 isoform. Consistently, mutation of C - TAD reduces cellular migration and proliferation. Mechanistically, selective binding of TAp73 (3 to DNAJA1 is required for the transactivation of C - TAD target genes, and silencing DNAJA1 expression abrogated all C - TAD - mediated effects. Taken together, our results provide a mechanistic basis for the dichotomous functions of TAp73 in the regulation of cellular growth through its distinct TADs.