Human Molecular Genetics, 2003, Vol. 12, No. 6 679-684
© 2003 Oxford University Press
BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels
1Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine and Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, 43210, USA and 2Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK
Received December 9, 2002; Accepted January 21, 2003
The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein and phosphatidylinositiol substrates and modulates cellular functions such as migration and proliferation. Germline mutations of PTEN have been shown to cause Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome and Proteus syndrome. Recently, germline mutations in BMPR1A, the gene encoding the type 1A receptor of bone morphogenetic proteins (BMP) have been found in rare families with Cowden syndrome, suggesting that there may be a link between BMP signaling and PTEN. We thus sought to determine whether BMP2 stimulation alters PTEN protein levels in the breast cancer line, MCF-7. We found that exposure to BMP2 increased PTEN protein levels in a time- and dose-dependent manner. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, as cycloheximide treatment did not inhibit BMP2-induced PTEN accumulation, suggesting that BMP2 stimulation inhibited PTEN protein degradation. Indeed, we found that BMP2 treatment of MCF-7 cells decreased the association of PTEN with two proteins in the degradative pathway, UbCH7 and UbC9. These data indicate that BMP2 exposure can regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway. This opens up a new mode of regulating PTEN activity to be investigated further and may explain why BMPR1A can act as a minor susceptibility gene for PTEN mutation negative Cowden syndrome.
* To whom correspondence should be addressed at: Human Cancer Genetics Program, The Ohio State University, 420 W. 12th Avenue, Suite 690TMRF, Columbus, OH 43210, USA. Tel: +1 6142922347; Fax: +1 6146883582 or 6146883205; Email: eng-1{at}medctr.osu.edu
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