Human Molecular Genetics, Vol 8, 185-193, Copyright © 1999 by Oxford University Press
PL Dahia, RC Aguiar, J Alberta, JB Kum, S Caron, H Sill, DJ Marsh, J Ritz, A Freedman, C Stiles and C Eng
PTEN is a novel tumour suppressor gene that encodes a dual-specificity
phosphatase with homology to adhesion molecules tensin and auxillin. It
recently has been suggested that PTEN dephosphorylates phosphatidylinositol
3,4,5-trisphosphate [PtdIns(3, 4,5)P3], which mediates growth
factor-induced activation of intracellular signalling, in particular
through the serine-threonine kinase Akt, a known cell survival-promoting
factor. PTEN has been mapped to 10q23.3, a region disrupted in several
human tumours including haematological malignancies. We have analysed PTEN
in a series of primary acute leukaemias and non-Hodgkin's lymphomas (NHLs)
as well as in cell lines. We have also examined whether a correlation could
be found between PTEN and Akt levels in these samples. We show here that
the majority of cell lines studied carries PTEN abnormalities. At the
structural level, we found mutations and hemizygous deletions in 40% of
these cell lines, while a smaller number of primary haematological
malignancies, in particular NHLs, carries PTEN mutations. Moreover,
one-third of the cell lines had low PTEN transcript levels, and 60% of
these samples had low or absent PTEN protein, which could not be attributed
to gene silencing by hypermethylation. In addition, we found that PTEN and
phosphorylated Akt levels are inversely correlated in the large majority of
the examined samples. These findings suggest that PTEN plays a role in the
pathogenesis of haematological malignancies and that it might be
inactivated through a wider range of mechanisms than initially considered.
The finding that PTEN levels inversely correlate with phosphorylated Akt
supports the hypothesis that PTEN regulates PtdIns(3,4,5)P3and suggests a
role for PTEN in apoptosis.
ARTICLES
PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin haematological malignancies
Departments of Adult Oncology and Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
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R. C.T. Aguiar, Y. Yakushijin, S. Kharbanda, S. Tiwari, G. J. Freeman, and M. A. Shipp PTPROt: An Alternatively Spliced and Developmentally Regulated B-Lymphoid Phosphatase That Promotes G0/G1 Arrest Blood, October 1, 1999; 94(7): 2403 - 2413. [Abstract] [Full Text] [PDF]
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T. W. Kelley, M. M. Graham, A. I. Doseff, R. W. Pomerantz, S. M. Lau, M. C. Ostrowski, T. F. Franke, and C. B. Marsh Macrophage Colony-stimulating Factor Promotes Cell Survival through Akt/Protein Kinase B J. Biol. Chem., September 10, 1999; 274(37): 26393 - 26398. [Abstract] [Full Text] [PDF]
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E.-M. Duerr, O. Gimm, D. S. Neuberg, J. B. Kum, S. C. Clifford, S. P. A. Toledo, E. R. Maher, P. L. M. Dahia, and C. Eng Differences in Allelic Distribution of Two Polymorphisms in the VHL-Associated Gene CUL2 in Pheochromocytoma Patients without Somatic CUL2 Mutations J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3207 - 3211. [Abstract] [Full Text]
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Y. Haseyama, K.-i. Sawada, A. Oda, K. Koizumi, H. Takano, T. Tarumi, M. Nishio, M. Handa, Y. Ikeda, and T. Koike Phosphatidylinositol 3-Kinase Is Involved in the Protection of Primary Cultured Human Erythroid Precursor Cells From Apoptosis Blood, September 1, 1999; 94(5): 1568 - 1577. [Abstract] [Full Text] [PDF]
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J. Torres and R. Pulido The Tumor Suppressor PTEN Is Phosphorylated by the Protein Kinase CK2 at Its C Terminus. IMPLICATIONS FOR PTEN STABILITY TO PROTEASOME-MEDIATED DEGRADATION J. Biol. Chem., January 5, 2001; 276(2): 993 - 998. [Abstract] [Full Text] [PDF]
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