Regulation of G1 Progression by the PTEN Tumor Suppressor Protein is Linked to Inhibition of the Phosphatidylinositol 3-kinase/Akt Pathway

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1999 Mar 3

PMID 10051603

Citations 246

Authors

S Ramaswamy

N Nakamura

F Vazquez

D B Batt

S Perera

T M Roberts

W R Sellers

Affiliations

Soon will be listed here.

Abstract

PTEN/MMAC1 is a tumor suppressor gene located on chromosome 10q23. Inherited PTEN/MMAC1 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 dual-specificity protein phosphatase and in addition can dephosphorylate certain lipid substrates. Herein, we show that PTEN protein induces a G1 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 G1. 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 G1 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-kinase/Akt pathway.

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References

Guldberg P, Thor Straten P, Birck A, Ahrenkiel V, Kirkin A, Zeuthen J . Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res. 1997; 57(17):3660-3. View

Furnari F, Huang H, Cavenee W . The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res. 1998; 58(22):5002-8. View

Kong D, Suzuki A, Zou T, Sakurada A, Kemp L, Wakatsuki S . PTEN1 is frequently mutated in primary endometrial carcinomas. Nat Genet. 1997; 17(2):143-4. DOI: 10.1038/ng1097-143. View

Rasheed B, Stenzel T, McLendon R, Parsons R, Friedman A, Friedman H . PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res. 1997; 57(19):4187-90. View

Datta S, Dudek H, Tao X, Masters S, Fu H, Gotoh Y . Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997; 91(2):231-41. DOI: 10.1016/s0092-8674(00)80405-5. View

del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 1997; 278(5338):687-9. DOI: 10.1126/science.278.5338.687. View

Chen C, Okayama H . High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987; 7(8):2745-52. PMC: 367891. DOI: 10.1128/mcb.7.8.2745-2752.1987. View

Tedder T, Isaacs C . Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol. 1989; 143(2):712-7. View

Montine K, Sonenberg N . Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature. 1990; 345(6275):544-7. DOI: 10.1038/345544a0. View

10.

Lane H, Fernandez A, Lamb N, Thomas G . p70s6k function is essential for G1 progression. Nature. 1993; 363(6425):170-2. DOI: 10.1038/363170a0. View

11.

Chuang J, Lin D, Lin S . Molecular cloning, expression, and mapping of the high affinity actin-capping domain of chicken cardiac tensin. J Cell Biol. 1995; 128(6):1095-109. PMC: 2120419. DOI: 10.1083/jcb.128.6.1095. View

12.

Rasheed B, McLendon R, Friedman H, Friedman A, Fuchs H, Bigner D . Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25. Oncogene. 1995; 10(11):2243-6. View

13.

Gray I, Phillips S, Lee S, Neoptolemos J, Weissenbach J, Spurr N . Loss of the chromosomal region 10q23-25 in prostate cancer. Cancer Res. 1995; 55(21):4800-3. View

14.

Iliopoulos O, Kibel A, Gray S, Kaelin Jr W . Tumour suppression by the human von Hippel-Lindau gene product. Nat Med. 1995; 1(8):822-6. DOI: 10.1038/nm0895-822. View

15.

Ungewickell E, Ungewickell H, Holstein S, Lindner R, Prasad K, Barouch W . Role of auxilin in uncoating clathrin-coated vesicles. Nature. 1995; 378(6557):632-5. DOI: 10.1038/378632a0. View

16.

Cheng J, Ruggeri B, Klein W, Sonoda G, Altomare D, Watson D . Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A. 1996; 93(8):3636-41. PMC: 39663. DOI: 10.1073/pnas.93.8.3636. View

17.

Tonks N, Neel B . From form to function: signaling by protein tyrosine phosphatases. Cell. 1996; 87(3):365-8. DOI: 10.1016/s0092-8674(00)81357-4. View

18.

Alessi D, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P . Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996; 15(23):6541-51. PMC: 452479. View

19.

Flint A, Tiganis T, Barford D, Tonks N . Development of "substrate-trapping" mutants to identify physiological substrates of protein tyrosine phosphatases. Proc Natl Acad Sci U S A. 1997; 94(5):1680-5. PMC: 19976. DOI: 10.1073/pnas.94.5.1680. View

20.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275(5308):1943-7. DOI: 10.1126/science.275.5308.1943. View