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

Backman, Stéphanie A.; Ghazarian, Danny; So, Kelvin; Sánchez, Otto; Wagner, Kay Uwe; Hennighausen, Lothar; Suzuki, Akira; Tsao, Ming‐Sound; Chapman, William; Stambolic, Vuk; Mak, Tak W.

doi:10.1073/pnas.0308217100

Cited by 144 publications

(108 citation statements)

References 41 publications

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“…PTEN is one of the tumor suppressor genes commonly mutated in various advanced human cancers including glioblastomas, as well as prostate, breast, endometrial and renal cancers (Stambolic et al, 1998). Skin-specific PTEN knockout mice develop spontaneous skin tumors and show earlier onset of chemically induced skin carcinogenesis (Suzuki et al, 2003;Backman et al, 2004). Adenoviral delivery of PTEN suppresses the malignant phenotype of prostate and ovarian cancer cells (Minaguchi et al, 1999;Davies et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Huang

et al. 2006

Oncogene

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Ultraviolet A (UVA, 315-400 nm), constituting about 95% of ultraviolet irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to show direct actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resistance. As evidence of carcinogenic transformation, UVAlong-treated (24 J/cm 2 once/week for 18 weeks) HaCaT (ULTH) cells showed increased secretion of matrix metalloproteinase (MMP-9), overexpression of keratin 13, altered morphology and anchorage-independent growth. Malignant transformation was established by the production of aggressive squamous cell carcinomas after inoculation of ULTH cells into nude mice (NC r -nu). ULTH cells were resistant to apoptosis induced not only by UVA but also by UVB and arsenite, two other human skin carcinogens. ULTH cells also became resistant to apoptosis induced by etoposide, staurosporine and doxorubicin hydrochloride. Elevated phosphorylation of protein kinase B (PKB, also called AKT) and reduced expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were detected in ULTH cells. The resistance of ULTH cells to UVA-induced apoptosis was reversed by either inhibition of phosphatidylinositol 3-kinase (PI-3K) or adenovirus expression of PTEN or dominant negative AKT. These data indicate that UVA has carcinogenic potential in human keratinocytes and that the increased AKT signaling and decreased PTEN expression may contribute to this malignant transformation. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help identify biomarkers for UVA-induced skin malignancies.

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Section: Discussionmentioning

confidence: 99%

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Huang

et al. 2006

Oncogene

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“…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. In tissue-specific Pten knockout animals, loss of Pten led to cancer development in some animals, but not in others (21,22). For those tissues in which cancer was not observed, additional molecular events were needed to overturn the regulatory machinery of cell proliferation and survival (15).…”

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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“…A more severe reduction in epidermal layers and hair follicles at birth was reported in Akt1 À/À Akt2 À/À and Akt1 À/À Akt3 þ /À mutant mice (Peng et al, 2003;Yang et al, 2005), suggesting redundant functions among Akt family members in the skin. More intriguingly, the keratinocyte-specific deletion of Pten resulted in epidermal hyperplasia and accelerated hair morphogenesis during the postnatal period Backman et al, 2004). Using conditional activation of Akt Flow cytometric analysis of epidermal cells.…”

Section: Role Of Akt Signaling In Epidermal Stem Cells and Progenitorsmentioning

confidence: 99%

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

Murayama¹,

Kimura²,

Tarutani

et al. 2007

Oncogene

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Various common signaling pathways maintain tissue stem cells, including Notch and Wnt/b-catenin signals. Phosphoinositide-3 kinase (PI3K)/Akt signaling regulates the 'stemness' of several stem cells in culture, specifically in maintaining embryonic stem and neural stem cells, and in deriving embryonic germ cells from primordial germ cells. We examined the effect of Akt signaling in epidermal cells in transgenic mice expressing an Akt-Mer fusion protein whose kinase activity was conditionally activated by treatment with 4-hydroxytamoxifen (4OHT). The topical application of 4OHT to adult skin of the transgenic mice induced new hair growth in resting phase follicles. In addition, the mice showed hyperplasia in interfollicular epidermis (IFE) and hair follicles, which was presumably caused by the extensive proliferation of keratinocytes in basal layer of IFE and outer root sheath of hair follicles, respectively. The progenitor cell population increased consistently in 4OHT-treated transgenic mice. Our results show that PI3K/Akt signaling induces epidermal hyperplasia and proliferation of epidermal progenitors.

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

Cited by 144 publications

References 41 publications

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

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

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

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