TY - JOUR
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.M.
AU - Aguiar, Ricardo C.T.
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
N1 - Funding Information:
The authors thank Margaret Shipp and Nick Cross for providing some of the cell lines or cell line DNAs used in this study; Sig Verselis for assistance with cell culture; and the Molecular Biology Core Facility at the Dana-Farber Cancer Institute for running the sequencing gels. Donna Neuberg is acknowledged for statistical advice, and Oliver Gimm for his critical review of the manuscript. This study was supported by the Susan G. Komen Breast Cancer Foundation (to P.L.M.D. and C.E.), the American Cancer Society (RPG 97-064-02VM and RPG-98-211-01-CCE), the Concert for the Cure and a Barr Investigatorship (to C.E.). C.E. is the Lawrence and Susan Marx Investigator in Human Cancer Genetics.
PY - 1999
Y1 - 1999
N2 - 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.
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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U2 - 10.1093/hmg/8.2.185
DO - 10.1093/hmg/8.2.185
M3 - Article
C2 - 9931326
AN - SCOPUS:0032898096
SN - 0964-6906
VL - 8
SP - 185
EP - 193
JO - Human molecular genetics
JF - Human molecular genetics
IS - 2
ER -