PTEN function in mammalian cell size regulation

Backman, Stéphanie A.; Stambolic, Vuk; Mak, Tak W.

doi:10.1016/s0959-4388(02)00354-9

Cited by 79 publications

(67 citation statements)

References 61 publications

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“…However, Pten nullizygosity does not result in neoplastic proliferation of all cell types. Deletion of Pten in terminally differentiated brain and heart cells causes enlargement of these organs as a consequence of increased cell size (28,29). Thus, consistent with earlier studies in Drosophila, Pten functions as an important regulator of cell and organ size (28).…”

Section: Discussionsupporting

confidence: 85%

“…Loss of heterozygosity for Pten in these tumors implies that homozygous inactivation of Pten is necessary for development of neoplasias. Analysis of mice with tissue-specific deletion of both Pten alleles revealed that homozygous inactivation of Pten results in hyperproliferation and neoplasia in lymphoid tissues, gonads, breast, and neural stem cells (13)(14)(15)(26)(27)(28). Neoplastic changes in Pten-null lymphocytes, keratinocytes, neural cells, and mammary epithelial cells are also associated with a resistance to apoptotic stimuli.…”

Section: Discussionmentioning

confidence: 99%

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Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten

Backman

Ghazarian

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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144

103

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PTEN is a tumor suppressor gene mutated in various advanced human neoplasias, including glioblastomas and prostate, breast, endometrial, and kidney cancers. This tumor suppressor is a lipid phosphatase that negatively regulates cell survival and proliferation mediated by phosphatidylinositol 3-kinase͞protein kinase B signaling. Using the Cre-loxP system, we selectively inactivated Pten in murine tissues in which the MMTV-LTR promoter is active, resulting in hyperproliferation and neoplastic changes in Pten-null skin and prostate. These phenotypes had early onset and were completely penetrant. Abnormalities in Pten mutant skin consisted of mild epidermal hyperplasia, whereas prostates from these mice exhibited high-grade prostatic intraepithelial neoplasia (HGPIN) that frequently progressed to focally invasive cancer. These data demonstrate that Pten is an important physiological regulator of growth in the skin and prostate. Further, the early onset of HGPIN in Pten mutant males is unique to this animal model and implicates PTEN mutations in the initiation of prostate cancer. Consistent with high PTEN mutation rates in human prostate tumors, these data indicate that PTEN is a critical tumor suppressor in this organ.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten

Backman

Ghazarian

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

144

103

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“…4), suggesting dedifferentiation. Cell-size changes have accounted for hypertrophy phenotypes observed in multiple tissue-specific Pten knockout models (17). Several downstream molecules of the AKT pathwayincluding PRS6KB1, MTOR, EIF4EBP1, and RPS6-were involved in the control of protein synthesis and were shown to be regulators of cell size (17).…”

Section: Discussionmentioning

confidence: 99%

“…Aberration of AKT signaling resulted in hyperproliferation and hyperplasia in most PTEN-deficient tissues, with a few exceptions (15,17,20). PTEN is probably not a major regulator of cell proliferation in the initial segment because loss of Pten did not alter proliferation in younger knockout mice and only resulted in a moderate increase in cell proliferation from 16 wk onward.…”

Section: Discussionmentioning

confidence: 99%

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

Washington

Hinton

2014

Proc. Natl. Acad. Sci. U.S.A.

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Without a fully developed initial segment, the most proximal region of the epididymis, male infertility results. Therefore, it is important to understand the development and regulation of this crucial region. In addition to distinctively high activity levels of the components of the ERK pathway, which are essential for initialsegment differentiation, the initial segment exhibits high protein and activity levels of phosphatase and tensin homolog (PTEN). To understand the role of PTEN in the regulation of the initial segment, we generated a mouse model with a conditional deletion of Pten from the epithelial cells of the proximal epididymis from postnatal day 17 (P17) onward. Shortly after Pten deletion, hypertrophy of the proximal epididymis became evident. Loss of Pten resulted in activation of the AKT (protein kinase B) pathway components from P28 onward, which in turn gradually suppressed RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK signaling through the interaction between AKT and RAF1. Consistent with progressive changes in RAF1/ERK signaling, loss of Pten progressively altered cell shape, size, organization, proliferation, and survival in the initial-segment epithelium and resulted in dedifferentiation and extensive epithelial folding. Most importantly, knockout males progressively lost fertility and became infertile from 6 to 12 mo. Spermatozoa from older knockout mice showed a lower percentage of motility and a higher percentage of flagellar angulation compared with controls, suggesting compromised sperm maturation. Therefore, under normal physiological conditions, PTEN suppresses AKT activity to maintain activation of the RAF1/ERK signaling pathway, which in turn maintains normal function of the initial segment and therefore, normal sperm maturation.S permatozoa enter the epididymis from the testes as immotile cells that are incapable of fertilization. During epididymal transit, a complex process called sperm maturation allows for conversion of spermatozoa into motile and fertilization-competent cells. The long, convoluted epididymal duct-which is ∼6 m long in humans and 1 m in mice (1)-provides a luminal fluid microenvironment that is necessary for sperm maturation (2).It is apparent that the most proximal region of the epididymis, the initial segment, plays an important role in sperm maturation. C-ros oncogene 1 (Ros1) knockout male mice that lacked prepubertal differentiation of the epididymal initial segment were healthy but infertile (3). Spermatozoa from Ros1 knockouts showed flagellar angulation, a defect in sperm maturation (4). Therefore, it is important to examine the mechanisms by which the initial segment develops, functions normally, and contributes to normal sperm maturation.The initial segment exhibits high activity levels of the ERK pathway components. The ERK pathway [also known as the RAF (RAF proto-oncogene serine/threonine kinases)/MEK/ERK pathway] is an intracellular protein kinase cascade containing at least MAPK3 and/or MAPK1 (commonly known as ERK1 and ERK2), a MAPKK (com...

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“…37 As the TOR protein can be specifically inhibited by sirolimus, changes in TOR protein may lead to a method for suppressing the effects of upstream PTEN signals.…”

Section: Discussionmentioning

confidence: 99%

Missense mutation in the PTEN promoter of a patient with hemifacial hyperplasia

et al. 2015

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The cellular mechanisms involved in the asymmetric facial overgrowth syndrome, hemifacial hyperplasia (HFH), are not well understood. This study was conducted to compare primary cell cultures from hyperplastic and normal HFH bone for cellular and molecular differences. Primary cultures developed from biopsies of a patient with isolated HFH showed a twofold difference in cell size and cell number between hyperplastic and normal bone. Microarray data suggested a 40% suppression of PTEN (phosphatase-tensin homolog) transcripts. Sequencing of the PTEN gene and promoter identified novel C/G missense mutation (position À 1053) in the regulatory region of the PTEN promoter. Western blots of downstream pathway components showed an increase in PKBa/Akt1 phosphorylation and TOR (target of rapamcyin) signal. Sirolimus, an inhibitor of TOR, when added to overgrowth cells reversed the cell size, cell number and total protein differences between hyperplastic and normal cells. In cases of facial overgrowth, which involve PTEN/Akt/TOR dysregulation, sirolimus could be used for limiting cell overgrowth.

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PTEN function in mammalian cell size regulation

Cited by 79 publications

References 61 publications

Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten

Early onset of neoplasia in the prostate and skin of mice with tissue-specific deletion of Pten

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

Missense mutation in the PTEN promoter of a patient with hemifacial hyperplasia

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