Critical role of PICT-1, a tumor suppressor candidate, in phosphatidylinositol 3,4,5-trisphosphate signals and tumorigenic transformation.
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 (PIP(3)). Recent study revealed that PICT-1/GLTSCR2 bound to and stabilized PTEN protein in cells, implicating its roles in PTEN-governed PIP(3) 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 PIP(3) 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 PIP(3) 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).
Okahara
Fumiaki
F
Biomembrane Signaling Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
Itoh
Kouichi
K
Nakagawara
Akira
A
Murakami
Makoto
M
Kanaho
Yasunori
Y
Maehama
Tomohiko
T
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009447:Neuroblastoma / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C500712:NOP53 protein, human; D018129:Phosphatidylinositol Phosphates; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human