Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production

Kimura, Tohru; Suzuki, Akira; Fujita, Yukiko; Yomogida, Kentaro; Lomelı́, Hilda; Asada, Noriko; Ikeuchi, Megumi; Nagy, András; Mak, Tak W.; Nakano, Toru

doi:10.1242/dev.00392

Cited by 229 publications

(208 citation statements)

References 66 publications

(79 reference statements)

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“…Stem cells possess the capacity for self-renewal and to produce committed progenitors. Previously, we showed the roles of PI3K/Akt signaling in pluripotent stem cells; the derivation of EG cells from PGC is enhanced in the absence of Pten and activated Akt supports the undifferentiated state of ES cells (Kimura et al, 2003;Watanabe et al, 2006). In addition, the self-renewal of neural stem cells in neurosphere culture is enhanced in Pten-deficient mice (Groszer et al, 2001).…”

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

confidence: 82%

“…PI3K/Akt signaling regulates self-renewal and differentiation capacity in the following stem cell systems. The derivation of pluripotent embryonic germ (EG) cells from primordial germ cells (PGC) is enhanced in PGCspecific Pten-deficient mice (Kimura et al, 2003), and the self-renewal of neural stem cells increases in brainspecific Pten mutant mice (Groszer et al, 2001). In addition, the introduction of an active mutant of Akt maintains the pluripotency of mouse and primate embryonic stem (ES) cells without leukemia inhibitory factor and feeder cells, respectively (Watanabe et al, 2006).…”

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confidence: 99%

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

confidence: 82%

mentioning

confidence: 99%

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

Murayama¹,

Kimura²,

Tarutani

et al. 2007

Oncogene

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“…11 Mice with defects in the Pten gene spontaneously develop germ cell tumors, 26,27 and interestingly, a human PTEN germ line mutation has been described in an adolescent man with synchronous testicular and extragonadal germ cell tumor. 28 We therefore speculate that there may be a link between NKX3.1 and PTEN disruption also in testicular tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

NKX3.1 Expression Is Lost in Testicular Germ Cell Tumors

Skotheim

Korkmaz

Klokk

et al. 2003

The American Journal of Pathology

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NKX3.1 is a homeobox gene which exhibits prostate and testis specific expression. Loss of NKX3.1 expression has been implicated in prostate development and tumorigenesis, but the role of NKX3.1 in testis biology is not known. Here we show that NKX3.1 expression is dramatically down-regulated in testicular cancer of germ cell origin. Immunohistochemical analysis on a tissue microarray containing 510 testicular tissue samples indicate that NKX3.1 is expressed at high levels in normal germ cells and in carcinoma in situ, but is sharply decreased or absent in most seminomas and all embryonal carcinomas. However, NKX3.1 is expressed in a subset of the more differentiated nonseminomas. We provide evidence that these changes in NKX3.1 protein levels are mainly due to transcriptional effects. These results suggest that NKX3.1 is essential for normal testis function and that its loss of expression is highly associated with the invasive phenotype of testicular germ cell tumors. Testicular germ cell tumor (TGCT) is the most common malignancy among adolescents and young adult men in Western industrialized countries, and the incidence has increased dramatically over the past fifty years.

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“…Mutations of both Ras and PTEN play major roles in human tumorigenesis (1,34). Similarly, pten ϩ/Ϫ and tissue-specific pten Ϫ/Ϫ mice develop tumors in multiple organ systems (22,25,(35)(36)(37)(38), as do mice expressing activated Ras (39,40). Rasinduced tumorigenesis is often associated with increased PI3ЈK activity.…”

Section: Placental Defects In Pten ؉/؊ Embryos Are Associated With Elmentioning

confidence: 99%

grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten ^+/- mice

Cully

Elia²,

Ong³

et al. 2004

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

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PTEN is a tumor suppressor gene implicated in both sporadic cancers and inherited tumor-prone syndromes. Here we show that pten ؉/؊ mice display a partially penetrant embryonic lethality. This lethality is associated with defects in both neural and placental development. Notably, this lethality is completely rescued by grb2 haploinsufficiency. In contrast, grb2 heterozygosity did not alter tumorigenesis in either pten ؉/؊ or T cell-specific pten ؊/؊ mice. grb2 ؊/hypomorph murine embryonic fibroblasts (MEFs) show decreased activation of both PKB and Erk upon stimulation with epidermal growth factor, whereas grb2 ؊/hypomorph ;pten ؉/؊ MEFs activate PKB but not Erk normally. Similarly, grb2 ؊/hypomorph fibroblasts die in low serum, and this phenotype is rescued by pten haploinsufficiency. Activation of both PKB and Erk as well as survival in low serum-containing media are all rescued by reexpression of Grb2 containing mutations within the N-terminal Src homology 3 (SH3) domain, but not by C-terminal SH3 domain mutants. The N-terminal SH3 domain mutants fail to bind to Sos, whereas the C-terminal SH3 domain mutants fail to bind to Gab1, suggesting that Erk and PKB activation in fibroblasts in response to epidermal growth factor depends on Gab1 or other C-terminal SH3 domain-interacting proteins, but not on Sos. Thus, PTEN͞phospha-tidylinositol 3 kinase signaling requires Grb2 during both embryonic development and fibroblast survival, but Grb2 heterozygosity does not effect tumorigenesis in pten-deficient mice. In fibroblasts, survival signals emanating from the epidermal growth factor receptor appear to be PKB-dependent, and this activation depends on the C-terminal SH3 domain of Grb2, likely through the interaction of Grb2 with Gab1.

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Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production

Cited by 229 publications

References 66 publications

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

NKX3.1 Expression Is Lost in Testicular Germ Cell Tumors

grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten ^+/- mice

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Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production

Cited by 229 publications

References 66 publications

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

NKX3.1 Expression Is Lost in Testicular Germ Cell Tumors

grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten +/- mice

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grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in pten ^+/- mice