Regulation of G₁progression by thePTENtumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway

Abstract

PTEN͞MMAC1 is a tumor suppressor gene located on chromosome 10q23. Inherited PTEN͞MMAC1 mutations are associated with a cancer predisposition syndrome known as Cowden's disease. Somatic mutation of PTEN has been found in a number of malignancies, including glioblastoma, melanoma, and carcinoma of the prostate and endometrium. The protein product (PTEN) encodes a dualspecificity protein phosphatase and in addition can dephosphorylate certain lipid substrates. Herein, we show that PTEN protein induces a G 1 block when reconstituted in PTEN-null cells. A PTEN mutant associated with Cowden's disease (PTEN;G129E) has protein phosphatase activity yet is defective in dephosphorylating inositol 1,3,4,5-tetrakisphosphate in vitro and fails to arrest cells in G 1 . These data suggest a link between induction of a cell-cycle block by PTEN and its ability to dephosphorylate, in vivo, phosphatidylinositol 3,4,5-trisphosphate. In keeping with this notion, PTEN can inhibit the phosphatidylinositol 3,4,5-trisphosphate-dependent Akt kinase, a downstream target of phosphatidylinositol 3-kinase, and constitutively active, but not wild-type, Akt overrides a PTEN G 1 arrest. Finally, tumor cells lacking PTEN contain high levels of activated Akt, suggesting that PTEN is necessary for the appropriate regulation of the phosphatidylinositol 3-kinase͞Akt pathway.

The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells

“…Considerable controversy exists as to the e ects of PTEN on cell proliferation, viability and anoikis (Cheney et al, 1998(Cheney et al, , 1999Davies et al, 1998Davies et al, , 1999Furnari et al, 1997Furnari et al, , 1998Li and Sun, 1998;Stambolic et al, 1998;Podsypanina et al, 1999;Ramaswamy et al, 1999;Sun et al, 1999;Tian et al, 1999). In the current study, induced expression of PTEN in PTEN de®cient breast cancer cells, was associated with a marked decrease in the basal phosphorylation of AKT, p70S6 kinase, BAD, and GSK3a, alterations indicative of decreased activity and signaling through the PI3K pathway.…”

“…Enforced expression of PTEN has been reported to result in decreased cell proliferation and decreased tumorigenicity (Cheney et al, 1998(Cheney et al, , 1999Furnari et al, 1998;Li and Sun, 1998;Tamura et al, 1999;Tian et al, 1999), an observation attributed to the ability of PTEN to induce cell cycle arrest, apoptosis or anoikis, a form of apoptosis that occurs when cells are dissociated from their extracellular matrix (Davies et al, 1998(Davies et al, , 1999Frisch and Ruoslahti, 1997;Furnari et al, 1998;Li and Sun, 1998;Sun et al, 1999;Ramaswamy et al, 1999;Stambolic et al, 1998). However, a consensus has not been reached on whether the capacity of PTEN to modulate these processes is determined by cell lineage or culture conditions.…”

“…Similarly, the biochemical mechanisms whereby PTEN in¯uences cell behavior are not well understood. However, enforced expression of PTEN has been linked to the decreased phosphorylation or activity of AKT, BAD and 4E-BP1 proteins, which act downstream of PI3K in various signaling cascades (Datta et al, 1997;Davies et al, 1998Davies et al, , 1999Delcommenne et al, 1998;Haas-Kogan et al, 1998;Pap and Cooper, 1998;Wu et al, 1998;Tian et al, 1999;Ramaswamy et al, 1999) and increased expression of p27, which is also downstream of PI3K (Cheney et al, 1999;Sun et al, 1999).…”

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

“…As shown in Figure 4E, the luciferase activities of different 5 0 -truncated PTEN promoter constructs that contain the Egr1-binding site were reduced by E-cadherin loss, whereas the luciferase activity of a full-length construct with a mutated Egr1-binding site, pGL3-PTEN2526/427(mutEgr1), was low in both control and shEcad-transfected SKOV-3 cells. As E-cadherin regulates PTEN, which has previously been implicated in the suppression of cell growth (Ramaswamy et al, 1999;Sun et al, 1999), we investigated whether the overexpression of PTEN regulates cyclin D1 and p27 Kip1 protein levels. Transient transfection of SKOV-3 cells with PTEN decreased cyclin D1 and increased p27 Kip1 protein levels ( Figure 4F).…”

Nuclear inositol lipid metabolism: More than just second messenger generation?

“…It was found that PTEN pretreatment abolished the protective effect of NGF, even though it was not demonstrated that PTEN actually decreased the amount of PtdIns (3,4,5)P 3 . In this connection, a good control would be constituted, in our opinion, by a mutated PTEN lacking the lipid phosphatase activity [Ramaswamy et al, 1999]. Since NGF treatment stimulates migration of phosphorylated Akt to the nucleus of PC12 cells ], the role of nuclear Akt in the antiapoptotic action of NGF was also examined.…”