The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene.

PTEN/MMAC1 is a tumor suppressor gene that is mutated in a variety of cancers. PTEN encodes a phosphatase that recognizes phosphoprotein substrates and the phospholipid, phosphatidylinositol-3,4,5-triphosphate. PTEN inhibited cell growth and/or colony formation in all of the epithelial lines tested with one exception. The decrease in cellular proliferation was associated with an induction of apoptosis and an inhibition of signaling through the phosphatidylinositol 3'-kinase pathway. Akt/protein kinase B, a gene whose antiapoptotic function is regulated by phosphatidylinositol-3,4,5-triphosphate, was able to rescue cells from PTEN-dependent death. PTEN, therefore, appears to suppress tumor growth by regulating phosphatidylinositol 3'-kinase signaling.

[1]  C. Eng,et al.  Germline mutations in PTEN are present in Bannayan-Zonana syndrome , 1997, Nature Genetics.

[2]  C. Purdie,et al.  Thymocyte apoptosis induced by p53-dependent and independent pathways , 1993, Nature.

[3]  W. Fantl,et al.  Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. , 1995, Science.

[4]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[5]  D. Bar-Sagi,et al.  Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos. , 1998, Science.

[6]  Kenneth M. Yamada,et al.  Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. , 1998, Science.

[7]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[8]  W. Cavenee,et al.  Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Hong Sun,et al.  TEP 1 , Encoded by a Candidate Tumor Suppressor Locus , Is a Novel Protein Tyrosine Phosphatase Regulated by Transforming Growth Factor 1 @ ' , 1997 .

[10]  W. Cance,et al.  Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[11]  Phillip T. Hawkins,et al.  Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B , 1998, Current Biology.

[12]  P. Tsichlis,et al.  Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  A. Klippel,et al.  Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways , 1996, Molecular and cellular biology.

[14]  R. Parsons Phosphatases and tumorigenesis , 1998, Current opinion in oncology.

[15]  D. Lowy,et al.  N Terminus of Sos1 Ras Exchange Factor: Critical Roles for the Dbl and Pleckstrin Homology Domains , 1998, Molecular and Cellular Biology.

[16]  K. Kinzler,et al.  Apoptosis and APC in colorectal tumorigenesis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Bar-Sagi,et al.  The role of the PH domain in the signal‐dependent membrane targeting of Sos , 1997, The EMBO journal.

[18]  M. Oren,et al.  p53; from inductive signal to cellular effect. , 1997, Current opinion in genetics & development.

[19]  N. Shao,et al.  Induction of apoptosis by the tumor suppressor protein BRCA1. , 1996, Oncogene.

[20]  J. Downward Lipid-Regulated Kinases: Some Common Themes at Last , 1998, Science.

[21]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[22]  I. W. Cheney,et al.  Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. , 1998, Cancer research.

[23]  K. Kinzler,et al.  A simplified system for generating recombinant adenoviruses. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  F. McCormick,et al.  Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. , 1997, Science.

[25]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[26]  G. Mills,et al.  MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. , 1997, Cancer research.

[27]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.