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Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73.
Li, Dan; Kok, Catherine Yen Li; Wang, Chao; Ray, Debleena; Osterburg, Susanne; Dötsch, Volker; Ghosh, Sujoy; Sabapathy, Kanaga.
Afiliação
  • Li D; Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 168583, Singapore.
  • Kok CYL; Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 168583, Singapore.
  • Wang C; Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 168583, Singapore.
  • Ray D; Programme in Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore.
  • Osterburg S; Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University, Frankfurt am Main 60438, Germany.
  • Dötsch V; Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University, Frankfurt am Main 60438, Germany.
  • Ghosh S; Centre for Computational Biology & Programme in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore.
  • Sabapathy K; Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 168583, Singapore.
Proc Natl Acad Sci U S A ; 121(21): e2318591121, 2024 May 21.
Article em En | MEDLINE | ID: mdl-38739802
ABSTRACT
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 TAp73ß, a commonly expressed p73 isoform. Mutational disruption of this TAD significantly reduced TAp73ß'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 TAp73ß'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 DNp73ß isoform. Consistently, mutation of C-TAD reduces cellular migration and proliferation. Mechanistically, selective binding of TAp73ß 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação Transcricional / Proliferação de Células / Proteína Tumoral p73 / Domínios Proteicos Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação Transcricional / Proliferação de Células / Proteína Tumoral p73 / Domínios Proteicos Idioma: En Ano de publicação: 2024 Tipo de documento: Article