Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 3, Pages 1008-1013Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1318124111
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Funding
- National Institute of Health (NIH) [CA116097, CA122623, CA124820, CA125123]
- National High Technology Research and Development Program of China [2012AA020206]
- National Natural Science Foundation of China [81171920]
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Pituitary tumor transforming gene 1 (Pttg1) encodes the mammalian securin, which is an inhibitor of separase (a protease required for the separation of sister chromatids in mitosis and meiosis). PTTG1 is overexpressed in a number of human cancers and has been suggested to be an oncogene. However, we found that, in Pttg1-mutant females, the mammary epithelial cells showed increased proliferation and precocious branching morphogenesis. In accord with these phenotypic changes, progesterone receptor, cyclin D1, and Mmp2 were up-regulated whereas p21 (Cdkn1a) was down-regulated. These molecular changes provide explanation for the observed developmental defects, and suggest that Pttg1 is a tumor suppressor. Indeed, mice lacking Pttg1 developed spontaneous mammary tumors. Furthermore, in human breast tumors, PTTG1 protein levels were down-regulated and the reduction was significantly correlated with the tumor grade.
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