論文

2021年6月22日

TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis

Science Signaling
  • Mary L. Uribe
  • ,
  • Maik Dahlhoff
  • ,
  • Rajbir N. Batra
  • ,
  • Nishanth B. Nataraj
  • ,
  • Yuya Haga
  • ,
  • Diana Drago-Garcia
  • ,
  • Ilaria Marrocco
  • ,
  • Arunachalam Sekar
  • ,
  • Soma Ghosh
  • ,
  • Itay Vaknin
  • ,
  • Sacha Lebon
  • ,
  • Lior Kramarski
  • ,
  • Yasuo Tsutsumi
  • ,
  • Inpyo Choi
  • ,
  • Oscar M. Rueda
  • ,
  • Carlos Caldas
  • ,
  • Yosef Yarden

14
688
開始ページ
eabe6156
終了ページ
eabe6156
記述言語
掲載種別
研究論文(学術雑誌)
DOI
10.1126/scisignal.abe6156
出版者・発行元
American Association for the Advancement of Science (AAAS)

Unlike early transcriptional responses to mitogens, later events are less well-characterized. Here, we identified delayed down-regulated genes (DDGs) in mammary cells after prolonged treatment with epidermal growth factor (EGF). The expression of these DDGs was low in mammary tumors and correlated with prognosis. The proteins encoded by several DDGs directly bind to and inactivate oncoproteins and might therefore act as tumor suppressors. The transcription factor teashirt zinc finger homeobox 2 (TSHZ2) is encoded by a DDG, and we found that overexpression of TSHZ2 inhibited tumor growth and metastasis and accelerated mammary gland development in mice. Although the gene <italic>TSHZ2</italic> localizes to a locus (20q13.2) that is frequently amplified in breast cancer, we found that hypermethylation of its promoter correlated with down-regulation of <italic>TSHZ2</italic> expression in patients. Yeast two-hybrid screens and protein-fragment complementation assays in mammalian cells indicated that TSHZ2 nucleated a multiprotein complex containing PRC1/Ase1, cyclin B1, and additional proteins that regulate cytokinesis. TSHZ2 increased the inhibitory phosphorylation of PRC1, a key driver of mitosis, mediated by cyclin-dependent kinases. Furthermore, similar to the tumor suppressive transcription factor p53, TSHZ2 inhibited transcription from the <italic>PRC1</italic> promoter. By recognizing DDGs as a distinct group in the transcriptional response to EGF, our findings uncover a group of tumor suppressors and reveal a role for TSHZ2 in cell cycle regulation.

リンク情報
DOI
https://doi.org/10.1126/scisignal.abe6156
URL
https://syndication.highwire.org/content/doi/10.1126/scisignal.abe6156
ID情報
  • DOI : 10.1126/scisignal.abe6156
  • ISSN : 1945-0877
  • eISSN : 1937-9145

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