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Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor

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Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor. / Berenjeno, Inma M.; Guillermet-Guibert, Julie; Pearce, Wayne; Gray, Alexander; Fleming, Stewart; Vanhaesebroeck, Bart.

In: Biochemical Journal, Vol. 442, 15.02.2012, p. 151-159.

Research output: Contribution to journalArticle

Harvard

Berenjeno, IM, Guillermet-Guibert, J, Pearce, W, Gray, A, Fleming, S & Vanhaesebroeck, B 2012, 'Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor' Biochemical Journal, vol 442, pp. 151-159., 10.1042/BJ20111741

APA

Berenjeno, I. M., Guillermet-Guibert, J., Pearce, W., Gray, A., Fleming, S., & Vanhaesebroeck, B. (2012). Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor. Biochemical Journal, 442, 151-159. 10.1042/BJ20111741

Vancouver

Berenjeno IM, Guillermet-Guibert J, Pearce W, Gray A, Fleming S, Vanhaesebroeck B. Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor. Biochemical Journal. 2012 Feb 15;442:151-159. Available from: 10.1042/BJ20111741

Author

Berenjeno, Inma M.; Guillermet-Guibert, Julie; Pearce, Wayne; Gray, Alexander; Fleming, Stewart; Vanhaesebroeck, Bart / Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor.

In: Biochemical Journal, Vol. 442, 15.02.2012, p. 151-159.

Research output: Contribution to journalArticle

Bibtex - Download

@article{216fdb8f129b4d6380161c47775208db,
title = "Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor",
author = "Berenjeno, {Inma M.} and Julie Guillermet-Guibert and Wayne Pearce and Alexander Gray and Stewart Fleming and Bart Vanhaesebroeck",
year = "2012",
doi = "10.1042/BJ20111741",
volume = "442",
pages = "151--159",
journal = "Biochemical Journal",
issn = "0264-6021",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Both p110 alpha and p110 beta isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor

A1 - Berenjeno,Inma M.

A1 - Guillermet-Guibert,Julie

A1 - Pearce,Wayne

A1 - Gray,Alexander

A1 - Fleming,Stewart

A1 - Vanhaesebroeck,Bart

AU - Berenjeno,Inma M.

AU - Guillermet-Guibert,Julie

AU - Pearce,Wayne

AU - Gray,Alexander

AU - Fleming,Stewart

AU - Vanhaesebroeck,Bart

PY - 2012/2/15

Y1 - 2012/2/15

N2 - <p>The PI3K (phosphoinositide 3-kinase) pathway is commonly activated in cancer as a consequence of inactivation of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K signalling. In line with this important role of PTEN, mice that are heterozygous for a PTEN-null allele (PTEN+/- mice) spontaneously develop a variety of tumours in multiple organs. PTEN is a phosphatase with selectivity for PtdIns(3,4,5)P-3, which is produced by the class I isoforms of PI3K (p110 alpha, p110 beta, p110 gamma and p110 delta). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110 beta, and that p110 beta, but not p110 alpha, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110 alpha can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110 alpha-or p110 beta-selective inhibitors, we confirm that inactivation of p110 beta but not p110 alpha, inhibits prostate cancer development in PTEN+/- mice, but also find that p110 alpha inactivation protects from glomerulonephritis, pheochromocytoma and thyroid cancer induced by PTEN loss. This indicates that p110 alpha can modulate the impact of PTEN loss in disease and tumourigenesis. In primary and immortalized mouse fibroblast cell lines, both p110 alpha and p110 beta controlled steady-state PtdIns(3,4,5)P-3 levels and Akt signalling induced by heterozygous PTEN loss. In contrast, no correlation was found in primary mouse tissues between PtdIns(3,4,5)P-3 levels, PI3K/PTEN genotype and cancer development. Taken together, our results from the present study show that inactivation of either p110 alpha or p110 beta can counteract the impact of PTEN inactivation. The potential implications of these findings for PI3K-targeted therapy of cancer are discussed.</p>

AB - <p>The PI3K (phosphoinositide 3-kinase) pathway is commonly activated in cancer as a consequence of inactivation of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K signalling. In line with this important role of PTEN, mice that are heterozygous for a PTEN-null allele (PTEN+/- mice) spontaneously develop a variety of tumours in multiple organs. PTEN is a phosphatase with selectivity for PtdIns(3,4,5)P-3, which is produced by the class I isoforms of PI3K (p110 alpha, p110 beta, p110 gamma and p110 delta). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110 beta, and that p110 beta, but not p110 alpha, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110 alpha can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110 alpha-or p110 beta-selective inhibitors, we confirm that inactivation of p110 beta but not p110 alpha, inhibits prostate cancer development in PTEN+/- mice, but also find that p110 alpha inactivation protects from glomerulonephritis, pheochromocytoma and thyroid cancer induced by PTEN loss. This indicates that p110 alpha can modulate the impact of PTEN loss in disease and tumourigenesis. In primary and immortalized mouse fibroblast cell lines, both p110 alpha and p110 beta controlled steady-state PtdIns(3,4,5)P-3 levels and Akt signalling induced by heterozygous PTEN loss. In contrast, no correlation was found in primary mouse tissues between PtdIns(3,4,5)P-3 levels, PI3K/PTEN genotype and cancer development. Taken together, our results from the present study show that inactivation of either p110 alpha or p110 beta can counteract the impact of PTEN inactivation. The potential implications of these findings for PI3K-targeted therapy of cancer are discussed.</p>

U2 - 10.1042/BJ20111741

DO - 10.1042/BJ20111741

M1 - Article

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

VL - 442

SP - 151

EP - 159

ER -

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