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PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanismsin
P L Dahia1, R C Aguiar, J Alberta
1Departments of Adult Oncology and Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
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)P3and suggests a role for PTEN in apoptosis.
Insights
The tumor suppressor gene PTEN is frequently altered in hematological malignancies. PTEN inactivation inversely correlates with phosphorylated Akt, suggesting a role in cell survival and apoptosis regulation.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PTEN is a tumor suppressor gene encoding a dual-specificity phosphatase.
- PTEN dephosphorylates phosphatidylinositol 3,4,5-trisphosphate, regulating cell signaling pathways like Akt.
- The PTEN gene is located at 10q23.3, a region frequently disrupted in human cancers.
Purpose of the Study:
- To analyze PTEN alterations in hematological malignancies.
- To investigate the correlation between PTEN and Akt levels in these cancers.
- To explore the role of PTEN in the pathogenesis of leukemia and lymphomas.
Main Methods:
- Analysis of PTEN in primary acute leukemias, non-Hodgkin's lymphomas (NHLs), and cell lines.
- Detection of PTEN mutations, deletions, and transcript levels.
- Assessment of PTEN protein levels and correlation with phosphorylated Akt.
Main Results:
- PTEN abnormalities, including mutations and deletions, were found in 40% of cell lines and a subset of primary NHLs.
- Low PTEN transcript and protein levels were observed in one-third and 60% of cell lines, respectively.
- PTEN and phosphorylated Akt levels were inversely correlated in most samples, suggesting PTEN regulates the Akt pathway.
Conclusions:
- PTEN plays a significant role in the pathogenesis of hematological malignancies.
- PTEN inactivation occurs through various mechanisms beyond gene silencing.
- The inverse correlation between PTEN and phosphorylated Akt supports PTEN's role in regulating PtdIns(3,4,5)P3 and apoptosis.