Abstract
In human cancer, PTEN (Phosphatase and TENsin homolog on chromosome 10, also referred to as MMAC1 and TEP1) is a frequently mutated tumor suppressor gene. We have used the zebrafish as a model to investigate the role of Pten in embryonic development and tumorigenesis. The zebrafish genome encodes two pten genes, ptena and ptenb. Here, we report that both Pten gene products from zebrafish are functional. Target-selected inactivation of ptena and ptenb revealed that Ptena and Ptenb have redundant functions in embryonic development, in that ptena−/− and ptenb−/− mutants did not show embryonic phenotypes. Homozygous single mutants survived as adults and they were viable and fertile. Double homozygous ptena−/−ptenb−/− mutants died at 5 days post fertilization with pleiotropic defects. These defects were rescued by treatment with the phosphatidylinositol-3-kinase inhibitor, LY294002. Double homozygous embryos showed enhanced cellular proliferation. In addition, cell survival was dramatically enhanced in embryos that lack functional Pten upon γ-irradiation. Surprisingly, adult ptenb−/− zebrafish developed ocular tumors later in life, despite the expression of ptena in adult eyes. We conclude that whereas Ptena and Ptenb have redundant functions in embryonic development, they apparently do not have completely overlapping functions later in life. These pten mutant zebrafish represent a unique model to screen for genetic and/or chemical suppressors of Pten loss-of-function.
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References
Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P et al. (1996). Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15: 6541–6551.
Ali IU, Schriml LM, Dean M . (1999). Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 91: 1922–1932.
Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J et al. (2001). Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte–Duclos disease. Nat Genet 29: 396–403.
Cole LK, Ross LS . (2001). Apoptosis in the developing zebrafish embryo. Dev Biol 240: 123–142.
Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T et al. (2002). Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110: 737–749.
Croushore JA, Blasiole B, Riddle RC, Thisse C, Thisse B, Canfield VA . (2005). Ptena and ptenb genes play distinct roles in zebrafish embryogenesis. Dev Dyn 234: 911–921.
Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP . (1999). Impaired Fas response and autoimmunity in Pten+/− mice. Science 285: 2122–2125.
Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP . (1998). Pten is essential for embryonic development and tumour suppression. Nat Genet 19: 348–355.
Goberdhan DC, Paricio N, Goodman EC, Mlodzik M, Wilson C . (1999). Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev 13: 3244–3258.
Gregorieff A, Grosschedl R, Clevers H . (2004). Hindgut defects and transformation of the gastro-intestinal tract in Tcf4(−/−)/Tcf1(−/−) embryos. EMBO J 23: 1825–1833.
Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA et al. (2001). Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294: 2186–2189.
Kishimoto H, Hamada K, Saunders M, Backman S, Sasaki T, Nakano T et al. (2003). Physiological functions of Pten in mouse tissues. Cell Struct Funct 28: 11–21.
Li DM, Sun H . (1997). TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57: 2124–2129.
Li J, Simpson L, Takahashi M, Miliaresis C, Myers MP, Tonks N et al. (1998). The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res 58: 5667–5672.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947.
Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z et al. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16: 64–67.
Lieschke GJ, Currie PD . (2007). Animal models of human disease: zebrafish swim into view. Nat Rev Genet 8: 353–367.
Maehama T, Dixon JE . (1998). The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375–13378.
Marcus RC, Delaney CL, Easter Jr SS . (1999). Neurogenesis in the visual system of embryonic and adult zebrafish (Danio rerio). off. Vis Neurosci 16: 417–424.
Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ et al. (1997). Germline mutations in PTEN are present in Bannayan–Zonana syndrome. Nat Genet 16: 333–334.
Mayo LD, Dixon JE, Durden DL, Tonks NK, Donner DB . (2002). PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem 277: 5484–5489.
Mihaylova VT, Borland CZ, Manjarrez L, Stern MJ, Sun H . (1999). The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci USA 96: 7427–7432.
Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA et al. (1998). The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci USA 95: 13513–13518.
Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T et al. (1998). Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95: 29–39.
Stokoe D . (2001). Pten. Curr Biol 11: R502.
Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J et al. (1999). PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci USA 96: 6199–6204.
Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I et al. (1998). High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8: 1169–1178.
Taylor GS, Dixon JE . (2003). PTEN and myotubularins: families of phosphoinositide phosphatases. Methods Enzymol 366: 43–56.
Westerfield M . (1995). A Guide For the Laboratory Use of Zebrafish (Danio rerio). University of Oregon Press: Salem, OR.
Wienholds E, Schulte-Merker S, Walderich B, Plasterk RH . (2002). Target-selected inactivation of the zebrafish rag1 gene. Science 297: 99–102.
Wu ZX, Song TB, Li DM, Zhang XT, Wu XL . (2007). Overexpression of PTEN suppresses growth and induces apoptosis by inhibiting the expression of survivin in bladder cancer cells. Tumour Biol 28: 9–15.
Zhou XP, Marsh DJ, Morrison CD, Chaudhury AR, Maxwell M, Reifenberger G et al. (2003). Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte–Duclos disease in adults. Am J Hum Genet 73: 1191–1198.
Acknowledgements
We would like to thank John Verhees for initial work on the pten mutant zebrafish and Neeltje Mooy (Ophthalmology, Erasmus Medical Center, Rotterdam) for her pathological analysis of the ocular tumor sections. This work was supported, in part, by a grant from the National Institute of Health (JED). The pten mutants were generated as part of the ZF-MODELS Integrated Project in the 6th Framework Programme (Contract No. LSHG-CT-2003-503496) funded by the European Commission.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Faucherre, A., Taylor, G., Overvoorde, J. et al. Zebrafish pten genes have overlapping and non-redundant functions in tumorigenesis and embryonic development. Oncogene 27, 1079–1086 (2008). https://doi.org/10.1038/sj.onc.1210730
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DOI: https://doi.org/10.1038/sj.onc.1210730
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