Cell cycle-dependent nuclear export of phosphatase and tensin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade.
The tumor suppressor phosphatase and tensin homologue (PTEN) plays distinct growth-regulatory roles in the cytoplasm and nucleus. It has been shown to be preferentially localized to the nucleus in differentiated or resting cells, and to the cytoplasm in advanced tumor cells. Thus, the regulation of PTEN's subcellular localization seems to be critical to its tumor-suppressing functions. In this study, we showed that activation of the phosphoinositide-3-kinase (PI3K) pathway triggers PTEN's cell cycle-dependent chromosome region maintenance 1-mediated nuclear export, as PTEN was predominantly expressed in the cytoplasm of TSC2(-/-) mouse embryo fibroblasts or activated Akt mutant-transfected NIH3T3 cells. In contrast, dominant-negative mutants of Akt and pharmacologic inhibitors of PI3K, mTOR, and S6K1, but not of MEK, suppressed the nuclear export of PTEN during the G(1)-S transition. The nuclear-cytoplasmic trafficking of exogenous PTEN is likewise regulated by the PI3K cascade in PTEN-null U251MG cells. The nuclear export of PTEN could also be blocked by short interfering RNA to S6K1/2. In addition, PTEN interacts with both S6K1 and S6K2. Taken together, our findings strongly indicate that activation of the PI3K/Akt/mTOR/S6K cascade, specifically S6K1/2, is pivotal in regulating the subcellular localization of PTEN. This scenario exemplifies a reciprocal regulation between PI3K and PTEN that defines a novel negative-feedback loop in cell cycle progression.
Liu
Juinn-Lin
JL
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mao
Zhenyu
Z
LaFortune
Tiffany A
TA
Alonso
Marta M
MM
Gallick
Gary E
GE
Fueyo
Juan
J
Yung
W K Alfred
WK
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism
D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human