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Our research activities focus on understanding the mechanisms governing cell-cycle regulated gene transcription and the role of these proteins in tumorigenesis and differentiation. The cyclin D1 gene encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates the tumor suppressor protein pRB (retinoblastoma protein) resulting in release of the pRB binding proteins and transcription factors, E2Fs. Several cyclin dependent kinase inhibitors (CDKI), p16/p19 block this activity of cyclin D1. Cyclin D1 plays a critical role in tumorigenesis and differentiation. Because the abundance of the cyclin D1 gene is rate-limiting in progression through the cell-cycle in cells that contain the pRB protein, we have delineated the molecular mechanisms regulating the cyclin D1 gene. We demonstrated that cyclin D1 kinase (CDK) activity and cyclin D1 promoter activity is induced by oncogenes (p21ras, Rac, dbl, v-src, Neu-also known as ErbB-2), growth factors and G-protein coupled receptors. The transcription factors (E2Fs,JUN/Fos, CREB, ATF2/ETS), coactivators (p300/CBP,Brg/Brm1) and scaffolding proteins (JIP1, caveolins) coordinate this induction. Using retroviral and lentiviral expression systems we are examining the requirement for specific cyclins and CKI for induction and progression of breast and prostate tumors induced by oncogenes. These systems are used to examine treatment synergy with conventional therapies. We have developed tissue-specific inducible transgenic expression systems and are using this transgenic approach to examine the role of cyclin D1, the CDKI in breast and prostate cancer. Using knockout mice we are examining the role of CDKI in breast cancer induced by specific oncogenes and synergy with conventional therapies. Keywords: cyclin d1, signal transduction, breast cancer, prostate cancer, gene therapy | ||||
| Selected Publications Jiao X, Katiyar S, Willmarth NE, Liu M, Ma X, Flomenberg N, Lisanti MP, Pestell RG. C-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem. 2010 Jan 6; [Epub ahead of print]. ( Abstract ) Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, Chumley MJ, Zdunek S, Wang C, Holm T, Goff SP, Pettersson S, Pestell RG, Henkemeyer M, Frisén J. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell. 139(4):679-92, 2009. ( Abstract ) Wu K, Katiyar S, Li A, Liu M, Ju X, Popov VM, Jiao X, Lisanti MP, Casola A, Pestell RG. Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8. Proc Natl Acad Sci U S A. 105(19):6924-9, 2008. ( Abstract ) Liu M, Casimiro MC, Wang C, Shirley LA, Jiao X, Katiyar S, Ju X, Li Z, Yu Z, Zhou J, Johnson M, Fortina P, Hyslop T, Windle JJ, Pestell RG. p21CIP1 attenuates Ras- and c-Myc-dependent breast tumor epithelial mesenchymal transition and cancer stem cell-like gene expression in vivo. Proc Natl Acad Sci U S A. 106(45):19035-9, 2009. ( Abstract ) Yu Z, Wang C, Wang M, Li Z, Casimiro MC, Liu M, Wu K, Whittle J, Ju X, Hyslop T, McCue P, Pestell RG. A cyclin D1/microRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. J Cell Biol. 182(3):509-17, 2008. ( Abstract ) Wu K, Katiyar S, Li A, Liu M, Ju X, Popov VM, Jiao X, Lisanti MP, Casola A, Pestell RG. Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of interleukin-8. Proc Natl Acad Sci U S A. 105(19):6924-9, 2008. ( Abstract ) Jiao X, Katiyar S, Liu M, Mueller SC, Lisanti MP, Li A, Pestell TG, Wu K, Ju X, Li Z, Wagner EF, Takeya T, Wang C, Pestell RG. Disruption of c-Jun Reduces Cellular Migration and Invasion through Inhibition of c-Src and Hyperactivation of ROCK II Kinase. Mol Biol Cell. 19(4):1378-1390, 2008. ( Abstract ) Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, Zhang X, Albanese C, Balk S, Chang C, Fan S, Rosen E, Palvimo JJ, Jänne OA, Muratoglu S, Avantaggiati ML, Pestell RG. Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol. 23(23):8563-75, 2003. ( Abstract ) Albanese C, Hulit J, Sakamaki T, Pestell RG. Recent advances in inducible expression in transgenic mice. Semin Cell Dev Biol. 13(2):129-41, 2002. ( Abstract ) Neumeister P, Albanese C, Balent B, Greally J, Pestell RG. Senescence and epigenetic dysregulation in cancer. Int J Biochem Cell Biol. 34(11):1475-90, 2002. ( Abstract ) Tanaka H, Matsumura I, Ezoe S, Satoh Y, Sakamaki T, Albanese C, Machii T, Pestell RG, Kanakura Y. E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell. 9(5):1017-29, 2002. ( Abstract ) Fu M, Wang C, Wang J, Zhang X, Sakamaki T, Yeung YG, Chang C, Hopp T, Fuqua SA, Jaffray E, Hay RT, Palvimo JJ, Janne OA, Pestell RG. Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol Cell Biol. 22(10):3373-88, 2002. ( Abstract ) Wang C, Fu M, D'Amico M, Albanese C, Zhou JN, Brownlee M, Lisanti MP, Chatterjee VK, Lazar MA, Pestell RG. Inhibition of cellular proliferation through IkappaB kinase-independent and peroxisome proliferator-activated receptor gamma-dependent repression of cyclin D1. Mol Cell Biol. 21(9):3057-70, 2001. ( Abstract ) Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, Lisanti MP, Katzenellenbogen BS, Kato S, Hopp T, Fuqua SA, Lopez GN, Kushner PJ, Pestell RG. Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. J Biol Chem. 276(21):18375-83, 2001. ( Abstract ) Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, Deng HF, Amenta PS, Fineberg S, Pestell RG, Carrasco N. The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med. 6(8):871-8, 2000. ( Abstract ) Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem. 275(27):20853-60, 2000. ( Abstract ) Albanese C, D'Amico M, Reutens AT, Fu M, Watanabe G, Lee RJ, Kitsis RN, Henglein B, Avantaggiati M, Somasundaram K, Thimmapaya B, Pestell RG. Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis. J Biol Chem. 274(48):34186-95, 1999. ( Abstract ) Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG, Hung MC. Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A. 97(8):4262-6, 2000. ( Abstract ) Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG. Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol. 20(2):672-83, 2000. ( Abstract ) | ||||
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