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Gene Review

Pten  -  phosphatase and tensin homolog

Mus musculus

Synonyms: 2310035O07Rik, A130070J02Rik, AI463227, B430203M17Rik, MMAC1, ...
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Disease relevance of Pten

  • RESULTS: Cdx-2 expression correlates with PTEN along the length of the murine colon and in colonic polyps that develop in Pten(+/-) mice [1].
  • To determine whether somatically acquired EGFRvIII expression or Pten loss accelerates high-grade glioma development, we used a previously characterized RasB8 glioma-prone mouse strain, in which these specific genetic changes were focally introduced at 4 weeks of age [2].
  • This novel preclinical model of high-grade glioma will be useful in evaluating brain tumor therapies targeted to the pathways specifically dysregulated by EGFR expression or Pten loss [2].
  • Moreover, altered expression of Cd95 and Pten occurred concomitantly in 34 of 68 (50%) thymic lymphomas suggesting a coordinated mechanism of inactivation of these genes [3].
  • Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity [4].
  • the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function [5]
  • Despite no prior exposure to hormone ablation therapy, Pten null cells are tumorigenic in both male and female severe combined immunodeficiency mice [6].
  • These physiological differences in the Pten mutant mice were associated with hyperactivation of the PI3K/acute transforming retrovirus thymoma protein kinase pathway, decreased susceptibility to apoptosis, and increased proliferation of mutant granulosa cells [7].
  • EPA ameliorated steatohepatitis and development of HCC in Pten-deficient mice [8].

High impact information on Pten

  • Here we show that the concomitant inactivation of one Pten allele and one or both Cdkn1b alleles accelerates spontaneous neoplastic transformation and incidence of tumors of various histological origins [9].
  • Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse [9].
  • Our findings reveal the crucial relevance of the combined tumor-suppressive activity of Pten and p27(Kip1) through the control of cell-cycle progression [9].
  • Neurons lacking Pten expressed high levels of phosphorylated Akt and showed a progressive increase in soma size without evidence of abnormal proliferation [10].
  • Retraction: Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice [11].

Chemical compound and disease context of Pten


Biological context of Pten

  • Akt activation increased Bad phosphorylation and promoted Pten-/- cell survival [15].
  • p18 Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control [16].
  • Pten(+/-) mice develop endometrial neoplastic lesions with full penetrance, thus providing a model system to dissect the genetic and biochemical events leading to the transition from normal to hyperplastic and neoplastic endometrial epithelium [17].
  • Surprisingly, we also found that Jak2, a proto-oncogene located between Cd95 and Pten, was simultaneously inactivated in a significant fraction of the tumors analysed (24 of 34, 70.6%) [3].
  • In most tumors arising in Pten heterozygotes, the Pten wild-type allele was lost, suggesting that cells lacking Pten function have a growth advantage over cells retaining a wild type allele [18].

Anatomical context of Pten


Associations of Pten with chemical compounds

  • The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake [4].
  • Pten mutant mice are resistant to developing streptozotocin-induced diabetes [20].
  • Finally, we observe androgen independence of high-grade PIN lesions after androgen ablation of Nkx3.1(+/-); Pten(+/-) mice [21].
  • Additionally, MRS performed on the prostate epithelia of probasin-ErbB-2Delta x Pten(+/-) mice identified changes in the relative concentrations of the metabolites choline and citrate, which was not observed in TRAMP mice [22].
  • The levels and relative ratios of PI3K products, phosphatidylinositol (3,4) bisphosphate (PI(3,4)P(2)) and phosphatidylinositol (3,4,5) trisphosphate (PIP(3)), are regulated by inositol phosphatases such as Pten and SHIP [23].

Enzymatic interactions of Pten

  • A most notable finding is that tumorigenesis is accompanied by inactivation of phosphatase and tensin homolog deleted on chromosome 10 (Pten), activation of AKT, fast proliferation and nuclear accumulation of cyclin D1 [24].

Regulatory relationships of Pten


Other interactions of Pten

  • METHODS: The expression patterns for Cdx-2 and PTEN along wild-type mouse colon, as well as in colon tumors occurring in Pten(+/-) mice, were examined [1].
  • EXPERIMENTAL DESIGN: 1,25 D(3) (or vehicle) was delivered continuously to Nkx3.1; Pten mutant or control mice for a 4-month period beginning before (precancerous cohort) or after (cancerous cohort) these mice developed PIN [27].
  • The occurrence of tumors is accelerated in experiments that activate FGF proto-oncogenes or remove the tumor suppressor genes Pten or P53, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma [28].
  • H-ras mutation is normally a hallmark of DMBA-TPA-induced skin tumors, but 70% of carcinomas from Pten+/- mice do not exhibit this mutation, and in all cases have lost the wild-type Pten allele [29].
  • Thus, mTor is required for neuronal hypertrophy downstream of Pten deficiency, but is not required for maintenance of normal neuronal soma size. mTOR inhibitors may be useful therapeutic agents for diseases in brain resulting from PTEN deficiency such as Lhermitte-Duclos disease or glioblastoma multiforme [30].
  • The effects of the Pten mutation require intact function of the PI3K subunits p110gamma and p110delta [31].

Analytical, diagnostic and therapeutic context of Pten


  1. PTEN and TNF-alpha regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-kappaB-dependent pathway. Kim, S., Domon-Dell, C., Wang, Q., Chung, D.H., Di Cristofano, A., Pandolfi, P.P., Freund, J.N., Evers, B.M. Gastroenterology (2002) [Pubmed]
  2. High-grade glioma formation results from postnatal pten loss or mutant epidermal growth factor receptor expression in a transgenic mouse glioma model. Wei, Q., Clarke, L., Scheidenhelm, D.K., Qian, B., Tong, A., Sabha, N., Karim, Z., Bock, N.A., Reti, R., Swoboda, R., Purev, E., Lavoie, J.F., Bajenaru, M.L., Shannon, P., Herlyn, D., Kaplan, D., Henkelman, R.M., Gutmann, D.H., Guha, A. Cancer Res. (2006) [Pubmed]
  3. Evidence of a possible epigenetic inactivation mechanism operating on a region of mouse chromosome 19 in gamma-radiation-induced thymic lymphomas. Santos, J., Herranz, M., Fernández, M., Vaquero, C., López, P., Fernández-Piqueras, J. Oncogene (2001) [Pubmed]
  4. Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity. Wong, J.T., Kim, P.T., Peacock, J.W., Yau, T.Y., Mui, A.L., Chung, S.W., Sossi, V., Doudet, D., Green, D., Ruth, T.J., Parsons, R., Verchere, C.B., Ong, C.J. Diabetologia (2007) [Pubmed]
  5. Allele-specific tumor spectrum in pten knockin mice. Wang, H., Karikomi, M., Naidu, S., Rajmohan, R., Caserta, E., Chen, H.Z., Rawahneh, M., Moffitt, J., Stephens, J.A., Fernandez, S.A., Weinstein, M., Wang, D., Sadee, W., La Perle, K., Stromberg, P., Rosol, T.J., Eng, C., Ostrowski, M.C., Leone, G. Proc. Natl. Acad. Sci. U. S. A. (2010) [Pubmed]
  6. Murine cell lines derived from Pten null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development. Jiao, J., Wang, S., Qiao, R., Vivanco, I., Watson, P.A., Sawyers, C.L., Wu, H. Cancer Res. (2007) [Pubmed]
  7. Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. Fan, H.Y., Liu, Z., Cahill, N., Richards, J.S. Mol. Endocrinol. (2008) [Pubmed]
  8. Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice. Ishii, H., Horie, Y., Ohshima, S., Anezaki, Y., Kinoshita, N., Dohmen, T., Kataoka, E., Sato, W., Goto, T., Sasaki, J., Sasaki, T., Watanabe, S., Suzuki, A., Ohnishi, H. J. Hepatol. (2009) [Pubmed]
  9. Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C., Pandolfi, P.P. Nat. Genet. (2001) [Pubmed]
  10. Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Kwon, C.H., Zhu, X., Zhang, J., Knoop, L.L., Tharp, R., Smeyne, R.J., Eberhart, C.G., Burger, P.C., Baker, S.J. Nat. Genet. (2001) [Pubmed]
  11. Retraction: Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice. Komazawa, N., Matsuda, M., Kondoh, G., Mizunoya, W., Iwaki, M., Takagi, T., Sumikawa, Y., Inoue, K., Suzuki, A., Mak, T.W., Nakano, T., Fushiki, T., Takeda, J., Shimomura, I. Nat. Med. (2005) [Pubmed]
  12. Muscle-specific Pten deletion protects against insulin resistance and diabetes. Wijesekara, N., Konrad, D., Eweida, M., Jefferies, C., Liadis, N., Giacca, A., Crackower, M., Suzuki, A., Mak, T.W., Kahn, C.R., Klip, A., Woo, M. Mol. Cell. Biol. (2005) [Pubmed]
  13. Emergence of androgen independence at early stages of prostate cancer progression in nkx3.1; pten mice. Gao, H., Ouyang, X., Banach-Petrosky, W.A., Shen, M.M., Abate-Shen, C. Cancer Res. (2006) [Pubmed]
  14. Transcriptional profiling endometrial carcinomas microdissected from DES-treated mice identifies changes in gene expression associated with estrogenic tumor promotion. Kabbarah, O., Mallon, M.A., Pfeifer, J.D., Goodfellow, P.J. Int. J. Cancer (2006) [Pubmed]
  15. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Sun, H., Lesche, R., Li, D.M., Liliental, J., Zhang, H., Gao, J., Gavrilova, N., Mueller, B., Liu, X., Wu, H. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  16. p18 Ink4c and Pten constrain a positive regulatory loop between cell growth and cell cycle control. Bai, F., Pei, X.H., Pandolfi, P.P., Xiong, Y. Mol. Cell. Biol. (2006) [Pubmed]
  17. Akt-mediated phosphorylation and activation of estrogen receptor alpha is required for endometrial neoplastic transformation in Pten+/- mice. Vilgelm, A., Lian, Z., Wang, H., Beauparlant, S.L., Klein-Szanto, A., Ellenson, L.H., Di Cristofano, A. Cancer Res. (2006) [Pubmed]
  18. Deficiency of Pten accelerates mammary oncogenesis in MMTV-Wnt-1 transgenic mice. Li, Y., Podsypanina, K., Liu, X., Crane, A., Tan, L.K., Parsons, R., Varmus, H.E. BMC Mol. Biol. (2001) [Pubmed]
  19. Transforming acidic coiled coil 1 promotes transformation and mammary tumorigenesis. Cully, M., Shiu, J., Piekorz, R.P., Muller, W.J., Done, S.J., Mak, T.W. Cancer Res. (2005) [Pubmed]
  20. Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Kurlawalla-Martinez, C., Stiles, B., Wang, Y., Devaskar, S.U., Kahn, B.B., Wu, H. Mol. Cell. Biol. (2005) [Pubmed]
  21. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Abate-Shen, C., Banach-Petrosky, W.A., Sun, X., Economides, K.D., Desai, N., Gregg, J.P., Borowsky, A.D., Cardiff, R.D., Shen, M.M. Cancer Res. (2003) [Pubmed]
  22. In vivo magnetic resonance volumetric and spectroscopic analysis of mouse prostate cancer models. Fricke, S.T., Rodriguez, O., Vanmeter, J., Dettin, L.E., Casimiro, M., Chien, C.D., Newell, T., Johnson, K., Ileva, L., Ojeifo, J., Johnson, M.D., Albanese, C. Prostate (2006) [Pubmed]
  23. Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice. Moody, J.L., Pereira, C.G., Magil, A., Fritzler, M.J., Jirik, F.R. Genes Immun. (2003) [Pubmed]
  24. Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin. Qiao, W., Li, A.G., Owens, P., Xu, X., Wang, X.J., Deng, C.X. Oncogene (2006) [Pubmed]
  25. mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Hu, X., Pandolfi, P.P., Li, Y., Koutcher, J.A., Rosenblum, M., Holland, E.C. Neoplasia (2005) [Pubmed]
  26. Disruption of a single Pten allele augments the chemotactic response of B lymphocytes to stromal cell-derived factor-1. Fox, J.A., Ung, K., Tanlimco, S.G., Jirik, F.R. J. Immunol. (2002) [Pubmed]
  27. Vitamin d inhibits the formation of prostatic intraepithelial neoplasia in nkx3.1; pten mutant mice. Banach-Petrosky, W., Ouyang, X., Gao, H., Nader, K., Ji, Y., Suh, N., Dipaola, R.S., Abate-Shen, C. Clin. Cancer Res. (2006) [Pubmed]
  28. Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype. Podsypanina, K., Li, Y., Varmus, H.E. BMC medicine [electronic resource]. (2004) [Pubmed]
  29. Mutually exclusive mutations of the Pten and ras pathways in skin tumor progression. Mao, J.H., To, M.D., Perez-Losada, J., Wu, D., Del Rosario, R., Balmain, A. Genes Dev. (2004) [Pubmed]
  30. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Kwon, C.H., Zhu, X., Zhang, J., Baker, S.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  31. The Pten/PI3K pathway governs the homeostasis of Valpha14iNKT cells. Kishimoto, H., Ohteki, T., Yajima, N., Kawahara, K., Natsui, M., Kawarasaki, S., Hamada, K., Horie, Y., Kubo, Y., Arase, S., Taniguchi, M., Vanhaesebroeck, B., Mak, T.W., Nakano, T., Koyasu, S., Sasaki, T., Suzuki, A. Blood (2007) [Pubmed]
  32. Gene expression analysis reveals a signature of estrogen receptor activation upon loss of Pten in a mouse model of endometrial cancer. Lian, Z., De Luca, P., Di Cristofano, A. J. Cell. Physiol. (2006) [Pubmed]
  33. Essential role of Pten in body size determination and pancreatic beta-cell homeostasis in vivo. Nguyen, K.T., Tajmir, P., Lin, C.H., Liadis, N., Zhu, X.D., Eweida, M., Tolasa-Karaman, G., Cai, F., Wang, R., Kitamura, T., Belsham, D.D., Wheeler, M.B., Suzuki, A., Mak, T.W., Woo, M. Mol. Cell. Biol. (2006) [Pubmed]
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