PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies

Patricia L Dahia, Ricardo C Aguiar, John Alberta, Jennifer B. Kum, Stacey Caron, Heinz Sill, Debbie J. Marsh, Jerome Ritz, Arnold Freedman, Charles Stiles, Charis Eng

Research output: Contribution to journalArticle

257 Citations (Scopus)

Abstract

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)P3 and suggests a role for PTEN in apoptosis.

Original languageEnglish (US)
Pages (from-to)185-193
Number of pages9
JournalHuman Molecular Genetics
Volume8
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

Fingerprint

Hematologic Neoplasms
Cell Survival
Cell Line
Non-Hodgkin's Lymphoma
Dual-Specificity Phosphatases
PTEN Phosphohydrolase
Sequence Deletion
Protein-Serine-Threonine Kinases
Gene Silencing
Tumor Suppressor Genes
Intercellular Signaling Peptides and Proteins
Leukemia
Apoptosis
Mutation
phosphatidylinositol 3,4,5-triphosphate
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. / Dahia, Patricia L; Aguiar, Ricardo C; Alberta, John; Kum, Jennifer B.; Caron, Stacey; Sill, Heinz; Marsh, Debbie J.; Ritz, Jerome; Freedman, Arnold; Stiles, Charles; Eng, Charis.

In: Human Molecular Genetics, Vol. 8, No. 2, 1999, p. 185-193.

Research output: Contribution to journalArticle

Dahia, Patricia L ; Aguiar, Ricardo C ; Alberta, John ; Kum, Jennifer B. ; Caron, Stacey ; Sill, Heinz ; Marsh, Debbie J. ; Ritz, Jerome ; Freedman, Arnold ; Stiles, Charles ; Eng, Charis. / PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. In: Human Molecular Genetics. 1999 ; Vol. 8, No. 2. pp. 185-193.
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T1 - PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies

AU - Dahia, Patricia L

AU - Aguiar, Ricardo C

AU - Alberta, John

AU - Kum, Jennifer B.

AU - Caron, Stacey

AU - Sill, Heinz

AU - Marsh, Debbie J.

AU - Ritz, Jerome

AU - Freedman, Arnold

AU - Stiles, Charles

AU - Eng, Charis

PY - 1999

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AB - 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)P3 and suggests a role for PTEN in apoptosis.

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