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P53 and ?Np63? Coregulate the Transcriptional and Cellular Response to TGF? and BMP Signals.

ABSTRACT: The TGF? superfamily regulates a broad range of cellular processes, including proliferation, cell-fate specification, differentiation, and migration. Molecular mechanisms underlying this high degree of pleiotropy and cell-type specificity are not well understood. The TGF? family is composed of two branches: (i) TGF?s, activins, and nodals, which signal through SMAD2/3, and (ii) bone morphogenetic proteins (BMP), which signal through SMAD1/5/8. SMADs have weak DNA-binding affinity and rely on coactivators and corepressors to specify their transcriptional outputs. This report reveals that p53 and ?Np63? act as transcriptional partners for SMAD proteins and thereby influence cellular responses to TGF? and BMPs. Suppression of p53 or overexpression of ?Np63? synergistically enhance BMP-induced transcription. Mechanistically, p53 and ?Np63? physically interact with SMAD1/5/8 proteins and co-occupy the promoter region of inhibitor of differentiation (ID2), a prosurvival BMP target gene. Demonstrating further convergence of these pathways, TGF?-induced canonical BMP regulated transcription in a ?Np63?- and p53-dependent manner. Furthermore, bioinformatic analyses revealed that SMAD2/3 and ?Np63? coregulate a significant number of transcripts involved in the regulation of epithelial-to-mesenchymal transition. Thus, p53 and ?Np63? are transcriptional partners for a subset of TGF?- and BMP-regulated SMAD target genes in the mammary epithelium. Collectively, these results establish an integrated gene network of SMADs, p53, and ?Np63? that contribute to EMT and metastasis.This study identifies aberrant BMP activation as a result of p53 mutation or ?Np63? expression.

SUBMITTER: Balboni AL

PROVIDER: S-EPMC4398640 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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p53 and ΔNp63α Coregulate the Transcriptional and Cellular Response to TGFβ and BMP Signals.

Balboni Amanda L AL Cherukuri Pratima P Ung Matthew M DeCastro Andrew J AJ Cheng Chao C DiRenzo James J

Molecular cancer research : MCR 20150219 4

<h4>Unlabelled</h4>The TGFβ superfamily regulates a broad range of cellular processes, including proliferation, cell-fate specification, differentiation, and migration. Molecular mechanisms underlying this high degree of pleiotropy and cell-type specificity are not well understood. The TGFβ family is composed of two branches: (i) TGFβs, activins, and nodals, which signal through SMAD2/3, and (ii) bone morphogenetic proteins (BMP), which signal through SMAD1/5/8. SMADs have weak DNA-binding affin ...[more]

PMID: 25700283

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Project description:BackgroundThe DNA damage response (DDR) is a mechanism that protects cells against radiation-induced oxidative DNA damage by causing cell cycle arrest and apoptosis. TP63 is a member of the tumour suppressor TP53 gene family, and ΔNp63α, a TP63 splicing variant, is constitutively expressed in the stem cell-containing basal layer of stratified epithelial tissues, including the mammary gland, where it plays a critical role in stemness and tissue development. ΔNp63α has been reported to transcriptionally inhibit the tumour suppression protein p53. This p53-repressive activity may cause genomic instability in epithelial stem cells exposed to radiation. In this study, we analysed the inhibitory effect of ΔNp63α on radiation-induced DDR.MethodsTo elucidate the role of the p53-repressive effect of ΔNp63α in radiation response, we performed a p63-siRNA knockdown experiment using human mammary epithelial cells (HMECs) expressing ΔNp63α and then performed ectopic and entopic expression experiments using human induced pluripotent stem cells (hiPSCs). After irradiation, the expression of DDR-related genes and proteins in ΔNp63α-expressing and control cells was analysed by RT-qPCR, Western blotting, and flow cytometry.ResultsThe mRNA/protein expression levels of BAX and p21 were significantly increased in p63-siRNA-treated HMECs (sip63) after X-ray irradiation (4 Gy, 0.7 Gy/min) but not in scramble-siRNA treated HMECs (scr). Transcriptomic analysis showed decreased RNA expression of cell cycle-related genes and increased expression of programmed cell death-related genes in sip63 cells compared to scr cells. Furthermore, flow cytometric analysis revealed an increase in apoptotic cells and a decrease in 5-ethynyl-2´-deoxyuridine uptake in sip63 cells compared to scr cells. On the other hand, both the ectopic and entopic expression of ΔNp63α in apoptosis-sensitive hiPSCs reduced the expression levels of BAX after irradiation and significantly decreased the number of apoptotic cells induced by radiation.ConclusionTaken together, these results indicate that ΔNp63α represses p53-related radiation-induced DDR, thereby potentially causing genomic instability in epithelial stem cells.

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P53 and ?Np63? Coregulate the Transcriptional and Cellular Response to TGF? and BMP Signals.

Publications

p53 and ΔNp63α Coregulate the Transcriptional and Cellular Response to TGFβ and BMP Signals.

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