Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription Journal Article
| Authors: | Takeda, S.; Sasagawa, S.; Oyama, T.; Searleman, A. C.; Westergard, T. D.; Cheng, E. H.; Hsieh, J. J. |
| Article Title: | Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription |
| Abstract: | Head morphogenesis requires complex signal relays to enable precisely coordinated proliferation, migration, and patterning. Here, we demonstrate that, during mouse head formation, taspase1-mediated (TASP1-mediated) cleavage of the general transcription factor TFIIA ensures proper coordination of rapid cell proliferation and morphogenesis by maintaining limited transcription of the negative cell cycle regulators p16Ink4a and p19Arf from the Cdkn2a locus. In mice, loss of TASP1 function led to catastrophic craniofacial malformations that were associated with inadequate cell proliferation. Compound deficiency of Cdkn2a, especially p16Ink4a deficiency, markedly reduced the craniofacial anomalies of TASP1-deficent mice. Furthermore, evaluation of mice expressing noncleavable TASP1 targets revealed that TFIIA is the principal TASP1 substrate that orchestrates craniofacial morphogenesis. ChIP analyses determined that noncleaved TFIIA accumulates at the p16Ink4a and p19Arf promoters to drive transcription of these negative regulators. In summary, our study elucidates a regulatory circuit comprising proteolysis, transcription, and proliferation that is pivotal for construction of the mammalian head. |
| Keywords: | controlled study; unclassified drug; promoter region; nonhuman; comparative study; cell proliferation; mouse; cell cycle; disease association; cell maturation; protein degradation; animal experiment; animal model; protein; morphogenesis; genetic transcription; protein p53; clinical evaluation; cell migration; cell cycle arrest; cyclin dependent kinase inhibitor 2a; c57bl 6 mouse; interstitial collagenase; stromelysin; transcription factor otx2; dickkopf 1 protein; craniofacial malformation; matrix metalloproteinase 14; coordination; transcription factor iia; transcription factor iiaalpha beta; male; priority journal; article; craniofacial development; p19arf protein; taspase1 protein; transcription factor alfalpha beta; transcription factor etd2; transcription factor hesx1; transcription factor mll1; transcription factor mll2 |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 125 |
| Issue: | 3 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2015-03-02 |
| Start Page: | 1203 |
| End Page: | 1214 |
| Language: | English |
| DOI: | 10.1172/jci77075 |
| PROVIDER: | scopus |
| PUBMED: | 25664857 |
| PMCID: | PMC4362222 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
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