PMID- 10468583
OWN - NLM
STAT- MEDLINE
DCOM- 19991007
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 18
DP  - 1999 Aug 31
TI  - The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal
      region.
PG  - 10182-7
AB  - PTEN is a recently identified tumor suppressor inactivated in a variety of
      cancers such as glioblastoma and endometrial and prostate carcinoma. It contains 
      an amino-terminal phosphatase domain and acts as a phosphatidylinositol
      3,4,5-trisphosphate phosphatase antagonizing the activity of the
      phosphatidylinositol 3-OH kinase. PTEN also contains a carboxyl-terminal domain, 
      and we addressed the role of this region that, analogous to the amino-terminal
      phosphatase domain, is the target of many mutations identified in tumors.
      Expression of carboxyl-terminal mutants in PTEN-deficient glioblastoma cells
      permitted the anchorage-independent growth of the cells that otherwise was
      suppressed by wild-type PTEN. The stability of these mutants in cells was reduced
      because of rapid degradation. Although the carboxyl-terminal region contains
      regulatory PEST sequences and a PDZ-binding motif, these specific elements were
      dispensable for the tumor-suppressor function. The study of carboxyl-terminal
      point mutations affecting the stability of PTEN revealed that these were located 
      in strongly predicted beta-strands. Surprisingly, the phosphatase activity of
      these mutants was affected in correlation with the degree of disruption of these 
      structural elements. We conclude that the carboxyl-terminal region is essential
      for regulating PTEN stability and enzymatic activity and that mutations in this
      region are responsible for the reversion of the tumor-suppressor phenotype. We
      also propose that the molecular conformational changes induced by these mutations
      constitute the mechanism for PTEN inactivation.
FAU - Georgescu, M M
AU  - Georgescu MM
AD  - Laboratory of Molecular Oncology, The Rockefeller University, New York, NY 10021,
      USA. georgem@rockvax.rockefeller.edu
FAU - Kirsch, K H
AU  - Kirsch KH
FAU - Akagi, T
AU  - Akagi T
FAU - Shishido, T
AU  - Shishido T
FAU - Hanafusa, H
AU  - Hanafusa H
LA  - eng
GR  - T32 CA009673/CA/NCI NIH HHS/United States
GR  - CA09673/CA/NCI NIH HHS/United States
GR  - CA44356/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - COS Cells
MH  - Female
MH  - Genes, Tumor Suppressor
MH  - Glioblastoma
MH  - Humans
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - PTEN Phosphohydrolase
MH  - Phosphoric Monoester Hydrolases/*chemistry/genetics/*metabolism
MH  - Placenta/metabolism
MH  - Point Mutation
MH  - Protein Structure, Secondary
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - *Tumor Suppressor Proteins
PMC - PMC17863
EDAT- 1999/09/01 00:00
MHDA- 1999/09/01 00:01
CRDT- 1999/09/01 00:00
PHST- 1999/09/01 00:00 [pubmed]
PHST- 1999/09/01 00:01 [medline]
PHST- 1999/09/01 00:00 [entrez]
AID - 10.1073/pnas.96.18.10182 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10182-7. doi:
      10.1073/pnas.96.18.10182.