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Thomas Jefferson University - Richard G. Pestell, MD, PhD
Richard G. Pestell, MD, PhD

Cancer Biology
Thomas Jefferson University
Jefferson Medical College
Associate Dean, Cancer Programs

Professor and Chairman, Department of Cancer Biology

Director, Kimmel Cancer Center at Jefferson

Vice President, Oncology Services, Thomas Jefferson University Hospital
Mailing Address
233 S. 10th St., Room 1050
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-503-5692
Fax: 215-503-9334
director@kimmelcancercenter.org
Personal Web Site
Expertise and Research Interests
Molecular mechanisms and gene therapy of breast and prostate cancer.

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
Publications
  • Publications from PubMed
  • Selected Publications
  • 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, Janne OA, Muratoglu S, Avantaggiati ML, Pestell RG. Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol. 2003 Dec;23(23):8563-75.
  • Albanese C, Hulit J, Sakamaki T, Pestell RG. Recent advances in inducible expression in transgenic mice. Semin Cell Dev Biol. 2002 Apr;13(2):129-41.
  • Neumeister P, Albanese C, Balent B, Greally J, Pestell R. Senescence and epigenetic dysregulation in cancer. Int J Biochem Cell Biol. 2002 Nov;34(11):1475.
  • 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. 2002 May;9(5):1017-29.
  • 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. 2002 May;22(10):3373-88.
  • 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. 2001 May;21(9):3057-70.
  • 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. 2001 May 25;276(21):18375-83.
  • 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. 2000 Aug;6(8):871-8.
  • 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. 2000 Jul 7;275(27):20853-60.
  • Albanese C, Reutens AT, Bouzahzah B, Fu M, D'Amico M, Link T, Nicholson R, Depinho RA, Pestell RG. Sustained mammary gland-directed, ponasterone A-inducible expression in transgenic mice. FASEB J. 2000 May;14(7):877-84.
  • 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. 2000 Apr 11;97(8):4262-6.
  • Lee RJ, Albanese C, Fu M, D'Amico M, Lin B, Watanabe G, Haines GK 3rd, 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. 2000 Jan;20(2):672-83.
  • Jiao, X., Katiyar, S., Liu, M., Mueller, S., Lisanti, M., Li, A., Pestell, T., Wu, K., Ju, X., Li, Z., Wagner, E., Takeya, T., Wang, C., Pestell, R.G. Disruption of c-jun reduces cellular migration and invasion through inhibition of c-Src and hyperactivation of ROCK II kinase, Mol. Biol. Cell., 2008. 19(4):1378-1390.
  • Wu, K., Katiyar, S., Ju, X., Popov, V., Liu, M., Jiao, X., Li, A., Lisanti, M., Casola, A., Pestell, R.G. Dachshund inhibits oncogene-induced breast cancer cellular migration and invasion through suppression of Interleukin-8. Proc. Natl. Acad. Sci. U.S.A. (2008); 105(19); 6924-9.
  • Zuoren Yu, Chenguang Wang, Min Wang, Zhiping Li, Mathew Casimiro, Manran Liu, Kongming Wu, James Whittle, Xiaoming Ju, Peter MacCue, Richard G. Pestell. A cyclin D1/miRNA 17/20 regulatory feedback loop in control of breast cancer cell proliferation. (2008).
  • Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C, McCue PA, McBurney MW, Pestell RG. Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation. Cancer Res. 2011 Feb 1;71(3):964-75. Epub 2010 Dec 28.
  • Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M, Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast cancer stem cell function. J Biol Chem. 2011 Jan 21;286(3):2132-42. Epub 2010 Oct 11.
  • Zhou J, Liu Y, Zhang W, Popov VM, Wang M, Pattabiraman N, Sune C, Cvekl A, Wu K, Jiang J, Wang C, Pestell RG. Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1. J Biol Chem. 2010 Dec 17;285(51):40342-50. Epub 2010 Oct 18.
  • Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, Pestell RG. C-jun inhibits mammary apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.
  • Yu Z, Willmarth NE, Zhou J, Katiyar S, Wang M, Liu Y, McCue PA, Quong AA, Lisanti MP, Pestell RG. microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8231-6. Epub 2010 Apr 20.
  • 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 Mar 12;285(11):8218-26. Epub 2010 Jan 6.
  • Popov VM, Wu K, Zhou J, Powell MJ, Mardon G, Wang C, Pestell RG. The Dachshund gene in development and hormone-responsive tumorigenesis. Trends Endocrinol Metab. 2010 Jan;21(1):41-9. Epub 2009 Nov 5. Review.
  • 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. 2009 Nov 10;106(45):19035-9. Epub 2009 Oct 26.
  • Liu M, Ju X, Willmarth NE, Casimiro MC, Ojeifo J, Sakamaki T, Katiyar S, Jiao X, Popov VM, Yu Z, Wu K, Joyce D, Wang C, Pestell RG. Nuclear factor-kappaB enhances ErbB2-induced mammary tumorigenesis and neoangiogenesis in vivo. Am J Pathol. 2009 May;174(5):1910-20. Epub 2009 Apr 6.
  • Velasco-Velazquez MA, Yu Z, Jiao X, Pestell RG. Cancer stem cells and the cell cycle: targeting the drive behind breast cancer. Expert Rev Anticancer Ther. 2009 Mar;9(3):275-9.

Individual Expertise profile of Richard G. Pestell, MD, PhD, Copyright © Richard G. Pestell, MD, PhD.
Last Updated by Admin : Wednesday, December 28, 2011 10:31:53 AM



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