2. Academic Validation
  3. TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis

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

  • Sci Signal. 2021 Jun 22;14(688):eabe6156. doi: 10.1126/scisignal.abe6156.
Mary L Uribe 1,  Maik Dahlhoff 2,  Rajbir N Batra 3 4,  Nishanth B Nataraj 1,  Yuya Haga 1 5,  Diana Drago-Garcia 1,  Ilaria Marrocco 1,  Arunachalam Sekar 1,  Soma Ghosh 1,  Itay Vaknin 1,  Sacha Lebon 1,  Lior Kramarski 1,  Yasuo Tsutsumi 5 6,  Inpyo Choi 7,  Oscar M Rueda 3 8,  Carlos Caldas 3,  Yosef Yarden 9
Affiliations

Affiliations

  • 1 Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
  • 2 Institute of in vivo and in vitro Models, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
  • 3 Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK.
  • 4 Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 5 Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
  • 6 Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan.
  • 7 Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 306-809, South Korea.
  • 8 MRC Biostatistics Unit, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0RE, UK.
  • 9 Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. yosef.yarden@weizmann.ac.il.
PMID: 34158398 DOI: 10.1126/scisignal.abe6156
Abstract

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 TSHZ2 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 TSHZ2 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 PRC1 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z