Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1090954 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The transcription factor p73, a member of the p53 tumor-suppressor family, regulates cell death and also supports tumorigenesis, though 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 TAp73β, a commonly expressed p73 isoform. Mutational disruption of this TAD significantly reduced TAp73β’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 TAp73β’s transactivation activity. Expression profiling highlighted a unique set of targets involved in extracellular matrix-receptor interaction and focal adhesion to be regulated by the C-TAD, resulting in FAK phosphorylation, distinct from the N-TAD targets that are common to p53 and involved in growth inhibition. Interestingly, the C-TAD targets are also regulated by the oncogenic, amino-terminal deficient DNp73β isoform. Consistently, mutation of C-TAD reduces cellular migration and proliferation. Mechanistically, selective binding of TAp73β 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 cellular growth through its distinct TADs.
2024-05-07 | GSE262279 | GEO
Project description:The aim of the experiment was to analyse the gene expression differences between MEFs containing TAp73 or without TAp73, at basal levels in normal culture conditions, and upon treatment with hypoxia (by incubation in 1% oxygen) for 4 or 8 hrs. The analysis indicate that absence of TAp73 leads to changes in multiple cellular and biological processes.
2014-10-11 | GSE62236 | GEO
Project description:The aim of the experiment was to analyse the gene expression differences between MEFs containing TAp73 or without TAp73, at basal levels in normal culture conditions, and upon treatment with hypoxia (by incubation in 1% oxygen) for 4 or 8 hrs. The analysis indicate that absence of TAp73 leads to changes in multiple cellular and biological processes. TAp73-/- and Tap73+/+ MEFs that were untreated, or treated with hypoxia (in 1% oxygen) for 4 and 8 hours were used for gene expression analysis
2014-10-11 | E-GEOD-62236 | biostudies-arrayexpress
Project description:Although being essential to respiratory and reproductive tracts multiciliogenesis, TAp73 is dispensable for multiciliogenesis in the ventricles. TAp73 KO is accompanied by dramatic changes in ciliogenic microRNAs miR34bc and miR449 family members, suggestin TAp73 functions partially thorugh posttranscriptional nodes in brain ciliogenesis.
2019-05-21 | GSE108385 | GEO
Project description:Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73 (TAp73) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis was used to identify TAp73-regulated gene sets. The effects of TAp73 were analyzed in monolayer cell culture, 3D-tumoroid and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 was significantly upregulated in HCC, and its high expression indicated poor patient survival. The induced expression of TAp73 caused landscape expression changes including genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. HCC cells overexpressing TAp73 had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73 upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings strongly suggest that TAp73 is a major promoter of malignant dedifferentiation of HCC cells Hepatocellular carcinoma (HCC) is a highly complex and heterogeneous type of cancer. Hepatocyte dedifferentiation is one of the important steps in the development of HCC. However, its molecular mechanisms are not well known. In this study, we report that TAp73 which is the major transcriptionally active form of p73 is overexpressed in HCC. Mechanically, TAp73 suppresses the expression of the hepatocyte markers including CYP3A4, AFP, ALB, HNF4a, while increasing the expression of several cholangiocyte markers in HCC cell lines. In conclusion, this report reveals a pro-oncogenic role for TAp73 in liver cancer.
2021-03-10 | GSE162860 | GEO
Project description:Cancer stem cells (CSCs) are resistant to conventional chemotherapy and are hence responsible for cancer relapse. Pluripotency is a characteristic of CSCs which allows them to rapidly proliferate while maintaining the ability to differentiate into various lineages. We found that TAp73, but not its homologue p53, is required for the pluripotency of CSCs. TAp73 knockdown (KD) decreased SOD1 levels, increased ROS production and disturbed metabolism which induced differentiation and abrogated pluripotency in CSCs. TAp73 related decrease in pluripotency is linked to increased autophagy and senescence in CSCs. Furthermore, TAp73 KD also decreased the levels of pluripotency factor Sox-2 within heterogeneous cancer cell lines. Interestingly, TAp73-deficient CSCs strongly lose tumorigenic potential in mice and tumors that did form had significantly lower levels of SOD1 and pluripotency marker Oct4. Our findings reveal a unique role of TAp73 in CSCs development that is important to consider while devising future therapeutic strategies against cancer.
2019-03-05 | PXD005407 | Pride
Project description:The goal of this study is to use H3K4me3 signal to mark the promoter regions of the p73 gene. The p73 gene expresses TAp73 and DNp73 isoforms, which use two different promoters. H3K4me3 is generally associated with the promoter of a gene and, therefore, can be used to mark the promoters for TAp73 and DNp73.
2021-04-16 | GSE169716 | GEO
Project description:A core evolutionary function of the p53 family is to protect the genomic integrity of gametes. However, the role of p73 in the male germline is unknown. Here we uncover that TAp73 unexpectedly functions as adhesion and maturation factor of the seminiferous epithelium orchestrating spermiogenesis. TAp73KO and p73KO mice, but not M-NM-^TNp73KO mice, display a M-bM-^@M-^Xnear-empty seminiferous tubuleM-bM-^@M-^Y phenotype due to massive premature loss of immature germ cells. Its cellular basis are defective cell-cell adhesions of developing germ cells to Sertoli nurse cells, with secondary degeneration of Sertoli cells including the blood-testis-barrier, thereby disrupting the adhesive integrity and maturation of the germ epithelium. At the molecular level, TAp73, produced in germ cells, controls a coordinated transcriptional program of adhesion- and migration-related proteins including peptidase inhibitors, proteases, receptors and integrins required for germ-Sertoli cell adhesion and dynamic junctional restructuring. Thus, the testis emerges as unique organ with strict division of labor among all family members: p63 and p53 safeguard germline fidelity, while TAp73 ensures fertility by enabling sperm maturation. 3 mice each for control wildtype and TAp73 knockout mice
2014-03-07 | E-GEOD-52124 | biostudies-arrayexpress
Project description:We investigated the downstream mechanisms by which TAp73β regulate apoptosis.
2005-12-01 | E-MEXP-349 | biostudies-arrayexpress
Project description:A core evolutionary function of the p53 family is to protect the genomic integrity of gametes. However, the role of p73 in the male germline is unknown. Here we uncover that TAp73 unexpectedly functions as adhesion and maturation factor of the seminiferous epithelium orchestrating spermiogenesis. TAp73KO and p73KO mice, but not ΔNp73KO mice, display a ‘near-empty seminiferous tubule’ phenotype due to massive premature loss of immature germ cells. Its cellular basis are defective cell-cell adhesions of developing germ cells to Sertoli nurse cells, with secondary degeneration of Sertoli cells including the blood-testis-barrier, thereby disrupting the adhesive integrity and maturation of the germ epithelium. At the molecular level, TAp73, produced in germ cells, controls a coordinated transcriptional program of adhesion- and migration-related proteins including peptidase inhibitors, proteases, receptors and integrins required for germ-Sertoli cell adhesion and dynamic junctional restructuring. Thus, the testis emerges as unique organ with strict division of labor among all family members: p63 and p53 safeguard germline fidelity, while TAp73 ensures fertility by enabling sperm maturation.
2014-03-07 | GSE52124 | GEO