Mark W. Jackson, Ph.D.

Assistant Professor

Mailing Address:
2103 Cornell Rd.
WRB 3134
Cleveland, OH 44106-7288

phone: (216) 368-1276
fax: (216) 368-0494
email: Mark.W.Jackson@Case.edu

Biography
Mark Jackson graduated from Kent State University in 1996, and then joined the Biomedical Sciences Training Program at Wright State University. While there, he studied the regulation of p53 by Hdm2 and HdmX, obtaining his Ph.D. in Biochemistry and Molecular Biology in 2001. After completing his Ph.D., Dr. Jackson joined the lab of Dr. George Stark in the Molecular Genetics Department at the Cleveland Clinic, where he continued his studies of the p53 tumor suppressor. He also developed in vitro transformation models and forward genetic technologies that are currently used in his own lab to decipher the genetics of breast hyperplasia. Dr. Jackson joined the Department of Pathology and the Case Comprehensive Cancer Center in the fall of 2007.

Research
The Jackson laboratory focuses on genetic events that contribute to breast hyperplasia. We have developed a breast cancer model that starts with normal human mammary epithelial cells (HMECs), and utilizes four genetic alterations associated with breast cancer, including inactivation of two tumor suppressors, p16INK4a and p53, and elevated expression of MYC and oncogenic HER2 or RAS. The resulting cells grow anchorage-independently, and possess hallmarks associated with cancer cells. Using this model we can interrogate the contribution of breast specific tumor-suppressive signaling and define how oncogene activation dismantles these suppressive signals to drive transformation and cancer progression. Current areas of focus include paracrine/autocrine TGF-beta, Oncostatin M, and Interferon signaling.

To identify novel proteins that can substitute for each of the known elements in HMEC transformation, we have developed a set of insertional mutagenesis lentiviral vectors (VBIM, validation-based insertional mutagenesis). Using the VBIM viruses we perform forward genetic screens to identify novel genetic alterations that can replace one of the four alterations that drive transformation in our model. By merging a powerful breast cancer model with an emerging technology we seek to identify signaling changes that occur during breast hyperplasia. We recently identified FAM83B (Family with Sequence Similarity 83, member B) based on its ability to substitute for RAS in the transformation of human mammary epithelial cells (HMECs). Interestingly, FAM83B is one of eight members of a protein family (FAM83) characterized by a highly conserved domain of unknown function (DUF1669), which is sufficient for HMEC transformation. FAM83B co-precipitates with CRAF, increasing CRAF membrane localization, and elevating MAPK, mTOR, and PLD signaling. Together these results suggest that FAM83 members constitute a novel oncogene family that provides vital new targets for therapeutic intervention that may significantly impact an oncologist's ability to treat cancer.

Publications
Jackson, M.W. and Berberich, S.J. (1999) Constitutive mdmx expression during cell growth, differentiation, and DNA damage. DNA Cell Biol. 18(9):693-700.

Jackson, M.W. and Berberich, S.J. (2000) MdmX protects p53 from Mdm2-mediated degradation. Mol. Cell. Biol. 20(3):1001-1007.

Jackson, M.W., Lindstrom, M. and Berberich, S.J. (2001) MdmX binding to ARF affects Mdm2 protein stability and p53 transactivation. Journal of Biological Chemistry Jul 6;276(27):25336-41.

Jackson, M.W. and Berberich, S.J. (2001) MdmX modulation of the p53:Mdm2 regulatory feedback loop. Recent Research Developments in Cancer 3:173-188.

Jackson, M.W., Agarwal, M.L., Agarwal, M.K. Agarwal, A. Stanhope-Baker, P. Williams, B.R.G. and George R. Stark. Limited role of N-terminal phosphoserine residues in the activation of transcription by p53. Oncogene. 2004; 23(25):4477-87.

Kandel, E.S., Lu, T., Wan, Y., Agarwal, M.K., Jackson, M.W. and George R. Stark. Mutagenesis by reversible promoter insertion to study the activation of NFkB. Proc Natl Acad Sci U S A. 2005; 3;102(18):6425-30.

Mayo, L.D., Seo, Y.R., Jackson M.W., Smith M.L., Guzman, J.R., Koraonkar, C. and David B. Donner. Phosphorylation determines target gene selection by p53 and the cellular response to chemotherapy. J Biol Chem. 2005; 15;280(28):25953-59.

Jackson, M.W., Agarwal, M.K., Yang, J., Bruss, P., Uchiumia, T., Agarwal, M.L., Stark, G.R. and William R. Taylor. p130/p107/p 105Rb-dependent transcriptional repression during DNA-damage-induced cell cycle exit at G2. J Cell Sci 2005; 1:118(Pt9):1821-32.

Patton JT, Mayo LD, Singhi AD, Gudkov AV, Stark GR and Jackson MW. Levels of HdmX expression dictate the sensitivity of normal and transformed cells to Nutlin-3. Cancer Research 2006, 66(6):3169-76.

Jackson M.W., Patt L.E., LaRusch G.A., Donner D.B., Stark G.R. and Lindsey D. Mayo. Hdm2 Nuclear Export, Regulated by IGF-I/MAPK/p90Rsk Signaling, Mediates the Transformation of Human Cells. J Biol Chem. 2006. 281(24):16814-20.

LaRusch G.A., Jackson M.W., Dunbar J.D., Donner D. and Lindsey D. Mayo. Nutlin3 blocks Vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible Factor 1alpha and Hdm2. Cancer Res. 2007 Jan 15;67(2):450-4.

Agarwal M.K., Hastak K., Jackson M.W., Breit S.N., Stark G.R..and Munna L. Agarwal. Macrophage inhibitory cytokine 1 mediates a p53-dependent protective arrest in S phase in response to starvation for DNA precursors. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16278-83.

Date, D., Jacob, C., Bekier, M., Stiff, A., Jackson M.W. and William Taylor. Borealin is repressed in response to p53/Rb signaling. Cell Biol Int. 2007 Dec;31(12):1470-81.

Kan,C.E., Patton, J.T., Stark, G.R. and Jackson M.W. p53-Mediated Growth Suppression in Response to Nutlin-3 in Cyclin D1–Transformed Cells Occurs Independently of p21. Cancer Research. 2007; 67: (20). 9862-9868.

Hastak K, Paul RK, Agarwal MK, Thakur VS, Amin AR, Agrawal S, Sramkoski RM, Jacobberger JW, Jackson MW, Stark GR, Agarwal ML. DNA synthesis from unbalanced nucleotide pools causes limited DNA damage that triggers ATR-CHK1-dependent p53 activation. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6314-9.

Yang J, Song K, Krebs TL, Jackson MW, Danielpour D. Rb/E2F4 and Smad2/3 Link Survivin to TGF-induced Apoptosis and Tumor Progression. Oncogene. 2008 Sep 11;27(40):5326-38

Gama V, Gomez JA, Mayo LD, Jackson MW, Danielpour D, Song K, Haas AL, Laughlin MJ, Matsuyama S. Hdm2 is an Ubiquitin Ligase of Ku70 -Akt Promotes Cell Survival by Inhibiting Hdm2-dependent Ku70 Destabilization. Cell Death and Differentiation. 2009 May;16(5):758-69.

Gomez JA, Sun W, Gama V, Hajkova D, Yoshida T, Wu Z, Miyagi M, Pink JJ, Jackson MW, Danielpour D, Matsuyama S. The C-terminus of interferon gamma receptor beta chain (IFNgammaR2) has antiapoptotic activity as a Bax inhibitor. Cancer Biol Ther. 2009 Sep 20;8(18).

Lu T*, Jackson MW*, Singhi AD* (equal contribution), Kandel ES, Yang M, Zhang Y, Gudkov AV, Stark GR. Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NFkB. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16339-44.

De S, Cipriano R, Jackson MW, Stark GR. Overexpression of kinesins mediates docetaxel resistance in breast cancer cells. Cancer Res. 2009 Oct 15;69(20):8035-42.

Lu, T, Jackson, MW, Wang, B, Yang, M, Chance, M, Miyagi, M, Gudkov, AV, and Stark, GR. (2009). Regulation of NFkB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):46-51.

Cipriano R, Patton JT, Mayo LD and Jackson MW. Inactivation of p53 signaling by p73 or PTEN ablation results in a transformed phenotype that remains susceptible to Nutlin-3 mediated apoptosis. Cell Cycle. 2010 Apr 12;9(7).

Amin AR, Thakur VS, Gupta K, Jackson MW, Harada H, Agarwal MK, Shin DM, Wald DN, Agarwal ML.Restoration of p53 functions protects cells from concanavalin A-induced apoptosis. Mol Cancer Ther. 2010 Feb;9(2):471-9

Thakur VS, Ruhul Amin AR, Paul RK, Gupta K, Hastak K, Agarwal MK, Jackson MW, Wald DN, Mukhtar H, Agarwal ML. p53-Dependent p21-mediated growth arrest pre-empts and protects HCT116 cells from PUMA-mediated apoptosis induced by EGCG. Cancer Lett. 2010 Oct 28;296(2):225-32.

Rocky Cipriano, Charlene E. Kan, James Graham, David Danielpour, Martha R. Stampfer, and Mark W. Jackson. TGF-β signaling engages a ATM-CHK2-p53-independent RAS-induced senescence and prevents transformation in human mammary epithelial cells. Proc Natl Acad Sci U S A. 2011 May 24;108(21):8668-73.

Rocky Cipriano and Mark W. Jackson. Delineating oncogene/tumor suppressor interactions in human mammary epithelial cells. Cell Cycle. 2011 Aug 15;10(16).

Cipriano R, Graham J, Miskimen KL, Bryson BL, Bruntz RC, Scott SA, Brown HA, Stark GR, and Jackson MW. FAM83B mediates EGFR- and RAS-driven oncogenic transformation. J Clin Invest. 2012, Aug 13

Kan CE, Cipriano R, and Jackson MW. c-MYC Functions as a Molecular Switch to Alter the Response of Human Mammary Epithelial Cells to Oncostatin M. Cancer Res. 2011 Nov 8.