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Vol. 17, Issue 11, 4888-4895, November 2006

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

Fumiaki Okahara^*,,, Kouichi Itoh, Akira Nakagawara^||, Makoto Murakami^*,¶, Yasunori Kanaho, and Tomohiko Maehama^*,

*Biomembrane Signaling Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan; Department of Physiological Chemistry, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan; Laboratory of Molecular Pharmacology, Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa 769-2193, Japan; ^||Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan; and ^¶PRESTO, Japan Science and Technology Corporation, Saitama 332-0012, Japan

Submitted April 12, 2006; Revised August 10, 2006; Accepted August 31, 2006
Monitoring Editor: John York

The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (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. Furthermore, 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%) 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).

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-04-0301) on September 13, 2006.

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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