Tai/NCOA2 suppresses the Hedgehog pathway by directly targeting the transcription factor Ci/GLI

• 成果类型: Article
• 署名作者: Yu, Xuan; Wang, Xinyu; Ma, Kaize; Gao, Dongqing; Deng, Yanran; Zhou, Dafa; Ding, Wenhao; Zhao, Yunhe; Liu, Qingxin; Zhou, Zizhang
• 署名单位: Shandong Agricultural University; Jiangxi Normal University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14854
• DOI: 10.1073/pnas.2409380121
• 发表日期: 2024-11-19
• 关键词: steroid-receptor coactivator-1; cancer cell-growth; cubitus-interruptus; protein; binding; signal; src-1; phosphorylation; proliferation; mechanisms

摘要

The Hedgehog (Hh) pathway plays diverse roles in cellular processes by activating the transcription factor Cubitus interruptus (Ci). Abnormal regulation of this pathway has been linked to various human diseases. While previous studies have focused on how Ci is regulated in the cytoplasm, the control of nuclear Ci remains poorly understood. In this study, we have found that the transcriptional cofactor Taiman (Tai) functions as an inhibitor of the Hh pathway. Tai interferes with the response of Hh signal, rather than Hh secretion. Our epistatic analyses reveal that Tai works in parallel with Ci to reduce its activity, thereby counteracting organ overgrowth and the activation of target genes caused by Ci overexpression. Specifically, Tai interacts with Ci to decrease its binding to target gene promoters. The Hh signal weakens the interaction between Ci and Tai, releasing the inhibition on Ci. Importantly, this regulatory mechanism is conserved from Drosophila to mammalian cells. Moreover, NCOA1-3 are the mammalian ortholog of Drosophila protein Tai, but only NCOA2 plays a similar role in inhibiting the Hh pathway. These findings reveal an additional way to modulate the transcriptional activity of nuclear Ci.