Abstract
PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3β and β-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3β, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3β/β-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.
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Abbreviations
- PTEN:
-
phosphatase and tensin homolog deleted on chromosome 10
- GSK3β:
-
glycogen synthase kinase 3β
- CRE:
-
cyclic AMP response element
- CREB:
-
CRE-binding protein
- FACS:
-
fluorescence-activated cell sorter
- PI3K:
-
phosphatidylinositol 3-kinase
- TCF:
-
T-cell factorr
- LEF:
-
lymphoid enhancer factor
References
Aberle H, Bauer A, Stappert J, Kispert A, Kemler R . (1997). Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16: 3797–3804.
Anzelon AN, Wu H, Rickert RC . (2003). Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nat Immunol 4: 287–294.
Barton K, Muthusamy N, Chanyangam M, Fischer C, Clendenin C, Leiden JM . (1996). Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB. Nature 379: 81–85.
Bullock BP, Habener JF . (1998). Phosphorylation of the cAMP response element binding protein CREB by cAMP-dependent protein kinase A and glycogen synthase kinase-3 alters DNA-binding affinity, conformation, and increases net charge. Biochemistry 37: 3795–3809.
Carthon BC, Neumann CA, Das M, Pawlyk B, Li T, Geng Y et al. (2005). Genetic replacement of cyclin D1 function in mouse development by cyclin D2. Mol Cell Biol 25: 1081–1088.
Chaganti RS, Houldsworth J . (2000). Genetics and biology of adult human male germ cell tumors. Cancer Res 60: 1475–1482.
Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH et al. (2002). Development of mice expressing a single D-type cyclin. Genes Dev 16: 3277–3289.
Datta SR, Brunet A, Greenberg ME . (1999). Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.
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.
Di Vizio D, Cito L, Boccia A, Chieffi P, Insabato L, Pettinato G et al. (2005). Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene 24: 1882–1894.
Diehl JA, Cheng M, Roussel MF, Sherr CJ . (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 12: 3499–3511.
Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM et al. (1997). Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275: 661–665.
Furnari FB, Lin H, Huang HS, Cavenee WK . (1997). Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci USA 94: 12479–12484.
Hsu SC, Galceran J, Grosschedl R . (1998). Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with beta-catenin. Mol Cell Biol 18: 4807–4818.
Huard JM, Forster CC, Carter ML, Sicinski P, Ross ME . (1999). Cerebellar histogenesis is disturbed in mice lacking cyclin D2. Development 126: 1927–1935.
Jena N, Deng M, Sicinska E, Sicinski P, Daley GQ . (2002). Critical role for cyclin D2 in BCR/ABL-induced proliferation of hematopoietic cells. Cancer Res 62: 535–541.
Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T et al. (2002). Identification of a Wnt/Dvl/beta-Catenin −> Pitx2 pathway mediating cell-type-specific proliferation during development. Cell 111: 673–685.
Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. (1997). Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science 275: 1784–1787.
Kozar K, Ciemerych MA, Rebel VI, Shigematsu H, Zagozdzon A, Sicinska E et al. (2004). Mouse development and cell proliferation in the absence of D-cyclins. Cell 118: 477–491.
Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H et al. (2002). Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis 32: 148–149.
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.
Liliental J, Moon SY, Lesche R, Mamillapalli R, Li D, Zheng Y et al. (2000). Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases. Curr Biol 10: 401–404.
Luo J, Manning BD, Cantley LC . (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4: 257–262.
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.
Marsh DJ, Dahia PL, Coulon V, Zheng Z, Dorion-Bonnet F, Call KM et al. (1998). Allelic imbalance, including deletion of PTEN/MMACI, at the Cowden disease locus on 10q22-23, in hamartomas from patients with Cowden syndrome and germline PTEN mutation. Genes Chromosomes Cancer 21: 61–69.
Mohamedali A, Soeiro I, Lea NC, Glassford J, Banerji L, Mufti GJ et al. (2003). Cyclin D2 controls B cell progenitor numbers. J Leukoc Biol 74: 1139–1143.
Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N . (1998). Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 273: 29864–29872.
Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H et al. (1997). Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet 6: 1383–1387.
Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW . (1997). Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. J Biol Chem 272: 24735–24738.
Parada Y, Banerji L, Glassford J, Lea NC, Collado M, Rivas C et al. (2001). BCR-ABL and interleukin 3 promote haematopoietic cell proliferation and survival through modulation of cyclin D2 and p27Kip1 expression. J Biol Chem 276: 23572–23580.
Persad S, Troussard AA, McPhee TR, Mulholland DJ, Dedhar S . (2001). Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation. J Cell Biol 153: 1161–1174.
Piatelli MJ, Wardle C, Blois J, Doughty C, Schram BR, Rothstein TL et al. (2004). Phosphatidylinositol 3-kinase-dependent mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 and NF-kappa B signaling pathways are required for B cell antigen receptor-mediated cyclin D2 induction in mature B cells. J Immunol 172: 2753–2762.
Pradeep A, Sharma C, Sathyanarayana P, Albanese C, Fleming JV, Wang TC et al. (2004). Gastrin-mediated activation of cyclin D1 transcription involves beta-catenin and CREB pathways in gastric cancer cells. Oncogene 23: 3689–3699.
Radu A, Neubauer V, Akagi T, Hanafusa H, Georgescu MM . (2003). PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Mol Cell Biol 23: 6139–6149.
Ravnik SE, Rhee K, Wolgemuth DJ . (1995). Distinct patterns of expression of the D-type cyclins during testicular development in the mouse. Dev Genet 16: 171–178.
Robker RL, Richards JS . (1998). Hormone-induced proliferation and differentiation of granulosa cells: a coordinated balance of the cell cycle regulators cyclin D2 and p27Kip1. Mol Endocrinol 12: 924–940.
Schmidt M, Fernandez de Mattos S, van der Horst A, Klompmaker R, Kops GJ, Lam EW et al. (2002). Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 22: 7842–7852.
Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M . (2000). Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103: 843–852.
Sharma M, Chuang WW, Sun Z . (2002). Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. J Biol Chem 277: 30935–30941.
Sherr CJ, Roberts JM . (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512.
Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY et al. (1996). Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 384: 470–474.
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.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH et al. (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15: 356–362.
Stiles B, Gilman V, Khanzenzon N, Lesche R, Li A, Qiao R et al. (2002). Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis. Mol Cell Biol 22: 3842–3851.
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.
Tetsu O, McCormick F . (1999). Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398: 422–426.
White PC, Shore AM, Clement M, McLaren J, Soeiro I, Lam EW et al. (2006). Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes. Oncogene 25: 2170–2180.
Wianny F, Real FX, Mummery CL, Van Rooijen M, Lahti J, Samarut J et al. (1998). G1-phase regulators, cyclin D1, cyclin D2, and cyclin D3: up-regulation at gastrulation and dynamic expression during neurulation. Dev Dyn 212: 49–62.
Xiong Y, Menninger J, Beach D, Ward DC . (1992). Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins. Genomics 13: 575–584.
Xu L, Corcoran RB, Welsh JW, Pennica D, Levine AJ . (2000). WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev 14: 585–595.
Zhu X, Kwon CH, Schlosshauer PW, Ellenson LH, Baker SJ . (2001). PTEN induces G(1) cell cycle arrest and decreases cyclin D3 levels in endometrial carcinoma cells. Cancer Res 61: 4569–4575.
Acknowledgements
We are grateful to Drs Hans C Clevers, Shengcai Lin, Huaxi Xu, Yongfeng Shang for plasmids, Fuming Lin for technical assistance. This work was supported by grants from the National Science Foundation of China (Grant #30430360, 30428005), 973 Program (2004CB720002) and SRFDP of the Ministry of Education of China (20030003087) to YGC.
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Huang, W., Chang, H., Fei, T. et al. GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN. Oncogene 26, 2471–2482 (2007). https://doi.org/10.1038/sj.onc.1210033
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DOI: https://doi.org/10.1038/sj.onc.1210033
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