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MBC in Press, published online ahead of print September 13, 2006
Mol. Biol. Cell 10.1091/mbc.E06-04-0301

A more recent version of this article appeared on November 1, 2006
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Submitted on April 12, 2006
Revised on August 10, 2006
Accepted on August 31, 2006

Critical Role of PICT-1, a Tumor Suppressor Candidate, in Phosphatidylinositol 3,4,5-Trisphosphate Signals and Tumorigenic Transformation

Fumiaki Okahara,*{dagger}{ddagger} Kouichi Itoh,{sect} Akira Nakagawara,|| Makoto Murakami,*¶ Yasunori Kanaho,{dagger} and Tomohiko Maehama*{ddagger}

*Biomembrane Signaling Project, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan; {dagger}Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, 1-1-1 Ten-noudai, Tsukuba 305-8575, Japan; {sect}Laboratory of Molecular Pharmacology, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki-city, Kagawa 769-2193, Japan; ||Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan; PRESTO, Japan Science and Technology Corporation, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan

Monitoring Editor: John York

The tumor suppressor PTEN regulates diverse cellular functions by dephosphorylating the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP3). Recent study revealed that PICT-1/GLTSCR2 bound to and stabilized PTEN protein in cells, implicating its roles in PTEN-governed PIP3 signals. In this study, we demonstrate that RNA interference-mediated knockdown of PICT-1 in HeLa cells down-regulated endogenous PTEN and resulted in the activation of PIP3 downstream effectors, such as protein kinase B/Akt. Further, the PICT-1 knockdown promoted HeLa cell proliferation; however the proliferation of PTEN-null cells was not altered by the PICT-1 knockdown, suggesting its dependency on PTEN status. In addition, apoptosis of HeLa cells induced by staurosporine or serum-depletion was alleviated by the PICT-1 knockdown in the similar PTEN-dependent manner. Most strikingly, the PICT-1 knockdown in HeLa and NIH3T3 cells promoted anchorage-independent growth, a hallmark of tumorigenic transformation. Furthermore, PICT-1 was aberrantly expressed in 18 (41%) out of 44 human neuroblastoma specimens, and the PICT-1 loss was associated with reduced PTEN protein expression in spite of the existence of PTEN mRNA. Collectively, these results suggest that PICT-1 plays a role in PIP3 signals through controlling PTEN protein stability and the impairment in the PICT-1-PTEN regulatory unit may become a causative factor in human tumor(s).

{ddagger}Present address: Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.

Address correspondence to: Tomohiko Maehama (tmaehama{at}nih.go.jp)




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[Abstract] [Full Text] [PDF]


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