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TAF6delta orchestrates an apoptotic transcriptome profile and interacts functionally with p53.

ABSTRACT: BACKGROUND: TFIID is a multiprotein complex that plays a pivotal role in the regulation of RNA polymerase II (Pol II) transcription owing to its core promoter recognition and co-activator functions. TAF6 is a core TFIID subunit whose splice variants include the major TAF6alpha isoform that is ubiquitously expressed, and the inducible TAF6delta. In contrast to TAF6alpha, TAF6delta is a pro-apoptotic isoform with a 10 amino acid deletion in its histone fold domain that abolishes its interaction with TAF9. TAF6delta expression can dictate life versus death decisions of human cells. RESULTS: Here we define the impact of endogenous TAF6delta expression on the global transcriptome landscape. TAF6delta was found to orchestrate a transcription profile that included statistically significant enrichment of genes of apoptotic function. Interestingly, gene expression patterns controlled by TAF6delta share similarities with, but are not equivalent to, those reported to change following TAF9 and/or TAF9b depletion. Finally, because TAF6delta regulates certain p53 target genes, we tested and demonstrated a physical and functional interaction between TAF6delta and p53. CONCLUSION: Together our data define a TAF6delta-driven apoptotic gene expression program and show crosstalk between the p53 and TAF6delta pathways.

SUBMITTER: Wilhelm E

PROVIDER: S-EPMC2827470 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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TAF6delta orchestrates an apoptotic transcriptome profile and interacts functionally with p53.

Wilhelm Emmanuelle E Kornete Mara M Targat Brice B Vigneault-Edwards Jimmy J Frontini Mattia M Tora Laszlo L Benecke Arndt A Bell Brendan B

BMC molecular biology 20100122

<h4>Background</h4>TFIID is a multiprotein complex that plays a pivotal role in the regulation of RNA polymerase II (Pol II) transcription owing to its core promoter recognition and co-activator functions. TAF6 is a core TFIID subunit whose splice variants include the major TAF6alpha isoform that is ubiquitously expressed, and the inducible TAF6delta. In contrast to TAF6alpha, TAF6delta is a pro-apoptotic isoform with a 10 amino acid deletion in its histone fold domain that abolishes its interac ...[more]

PMID: 20096117

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Project description:BackgroundActivation of p53-mediated gene transcription is a critical cellular response to DNA damage and involves a phosphorylation-acetylation cascade of p53. The discovery of differences in the response to different agents raises the question whether some of the p53 oncosuppressor functions might be exerted by different posttranslational modifications. Stress-induced homeodomain-interacting protein kinase-2 (HIPK2) phosphorylates p53 at serine-46 (Ser46) for p53 apoptotic activity; p53 acetylation at different C-terminus lysines including p300-mediated lysine-382 (Lys382) is also required for full activation of p53 transcriptional activity. The purpose of the current study was to evaluate the interplay among HIPK2, p300, and p53 in p53 acetylation and apoptotic transcriptional activity in response to drug by using siRNA interference, p300 overexpression or deacetylase inhibitors, in cancer cells.ResultsKnockdown of HIPK2 inhibited both adriamycin-induced Ser46 phosphorylation and Lys382 acetylation in p53 protein; however, while combination of ADR and zinc restored Ser46 phosphorylation it did not recover Lys382 acetylation. Chromatin immunoprecipitation studies showed that HIPK2 was required in vivo for efficient p300/p53 co-recruitment onto apoptotic promoters and that both p53 modifications at Ser46 and Lys382 were necessary for p53 apoptotic transcription. Thus, p53Lys382 acetylation in HIPK2 knockdown as well as p53 apoptotic activity in response to drug could be rescued by p300 overexpression. Similar effect was obtained with the Sirt1-inhibitor nicotinamide. Interestingly trichostatin A (TSA), the inhibitor of histone deacetylase complexes (HDAC) did not have effect, suggesting that Sirt1 was the deacetylase involved in p53 deacetylation in HIPK2 knockdown.ConclusionThese results reveal a novel role for HIPK2 in activating p53 apoptotic transcription. Our results indicate that HIPK2 may regulate the balance between p53 acetylation and deacetylation, by stimulating on one hand co-recruitment of p300 and p53Lys382 on apoptotic promoters and on the other hand by inhibiting Sirt1 deacetylase activity. We attempted to reactivate p53 apoptotic transcriptional activity by rescuing both Ser46 and Lys382 modification in response to drug. Our data propose combination strategies for the treatment of tumors with dysfunctional p53 and/or HIPK2 that include classical chemotherapy with pharmacological or natural agents such as Sirt1-deacetylase inhibitors or zinc, respectively.

Dataset Information

TAF6delta orchestrates an apoptotic transcriptome profile and interacts functionally with p53.

Publications

TAF6delta orchestrates an apoptotic transcriptome profile and interacts functionally with p53.

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