University of South Florida

Cancer Biology Ph.D. Program at the

George Blanck, Ph.D. Professor, USF Molecular Medicine E-mail: gblanck@health.usf.edu Phone: 813-974-9585 USF Web Page: Click Here

Training
Undergraduate: University of Pennsylvania

Ph.D.: Columbia University

Postdoctoral Fellow: Harvard University

Research Interests

Our lab's long-term goals have been (i) to further understand molecular mechanisms of gene regulation and (ii) to further understand disease processes as they relate to pathological conditions of gene regulation.

To meet these goals, our lab is primarily dedicated toward the understanding of the interferon cell-signaling pathway in normal and tumor cells. The activation of this pathway leads to the expression of genes that inhibit tumor cell growth by at least several mechanisms. Consequently, tumors develop with defects in this pathway. We are in the process of using transgenic and knock-out mice to isolate specific branches of the inteferon pathway to determine exactly which consequences of the tumor defects are relevant to tumor development in tumor prone mice. Also, because of these tumor defects in inteferon mediated cell-signaling, human tumor cell lines represent tools for understanding the normal biochemical mechanisms of the signaling pathway. We have taken advantage of numerous tumor cell lines, defective for interferon signaling, to determine that proteins, not previously known to be relevant to this pathway's function, are indeed required for normal activation of the pathway. Most recently, this work has led to a novel mechanism of gene repression, involving a protein complex we have termed a "repressosome", representing a concept that will likely be applicable to other genes. As another example, we have learned that two proteins that were previously thought to have opposing effects in gene activation can instead cooperate in the activation of a gene. This led to the discovery of novel biochemical features of gene activation for these two proteins, termed IRF-1 and IRF-2.

We regard to both the repressosome and the IRF proteins, we expect that a more detailed understanding of the biochemical features of these protein complexes will allow drugs to be designed to mitigate disease processes. The repressosome is likely to be very specific for a particular gene that is not expressed in tumor cells. The re-expression of this gene could make the tumor cells less tumorigenic, thus drugs designed to disrupt the repressosome may reduce tumor burden. Small, cell-permeable molecules, related to drugs currently in use in medicine, have already been used to disrupt the repressosome. This disruption is accompanied by the re-establishment of specific gene expression. We have also recently learned that the IRF-2 protein is important in mice for interferon signaling, thus verifying that what we discovered in the experimental setting of cultured cells is applicable to a whole organism. Because of this result, we expect that IRF-2 will be a good drug target for mitigating immunity associated pathological conditions where the gene activated by IRF-2 is over-expressed, such as in autoimmunity or organ transplant rejection. Current drugs designed to meet this goal target broad aspects of the immune system leading to undesirable consequences, for example tumor development in transplant patients receiving immunosuppressive drugs. Thus, novel approaches to immunosuppression is an important goal.

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Selected Publications

Spies T, Bresnahan M, Bahram S, Arnold D, Blanck G, Mellins E, Pious D, Demars R. Pillars Article: A Gene in the Human Major Histocompatibility Complex Class II Region Controlling the Class I Antigen Presentation Pathway. Nature 1990. 348: 744-747.J Immunol. 2008 Mar 1;180(5):2737-40.

Palubin KM, Goodwin BL, Niesen MI, Le EA, Osborne AR, Blanck G. A direct mechanistic link between growth control and a tumor cell immune function: increased interleukin-8 secretion accounts for elimination of Oct-1 antisense transformants from scid mice. Anticancer Res. 2006 May-Jun;26(3A):1733-8.

Osborne AR, Zhang H, Blanck G. Oct-1 DNA binding activity unresponsive to retinoblastoma protein expression prevents MHC class II induction in a non-small cell lung carcinoma cell line. Mol Immunol. 2006 Feb;43(6):710-6. Epub 2005 Apr 14.

Le E, Zhang H, Blanck G. CIITA transformation rescues the apoptotic function of MHC class II in melanoma cells. Anticancer Res. 2005 Nov-Dec;25(6B):3889-92.

Niesen MI, Osborne AR, Yang H, Rastogi S, Chellappan S, Cheng JQ, Boss JM, Blanck G.
Activation of a methylated promoter mediated by a sequence-specific DNA-binding protein, RFX. J Biol Chem. 2005 Nov 25;280(47):38914-22. Epub 2005 Sep 15.

Osborne AR, Zhang H, Fejer G, Palubin KM, Niesen MI, Blanck G. Oct-1 maintains an intermediate, stable state of HLA-DRA promoter repression in Rb-defective cells: an Oct-1-containing repressosome that prevents NF-Y binding to the HLA-DRA promoter.
J Biol Chem. 2004 Jul 9;279(28):28911-9. Epub 2004 Apr 22.

D. D. Eason, C. Lebron, D. Coppola, L. C. Moscinski, S. Livingston, E. T. Sutton, and G. Blanck. Development of CD30+ lymphoproliferative disease in mice lacking interferon regulatory factor-1. Oncogene 22 (40): 6166-6176 (2003).

H. Xi and G. Blanck. The IRF-2 DNA binding domain facilitates the activation of the class II transactivator (CIITA) Type IV Promoter by IRF-1. Molecular Immunology 39(11): 677-684 (2003).

George Blanck. Components of the IFN-g signaling pathway in tumorigenesis. Achivum Immunologiae and Therapiae Experimentalis 50(3):151-158 (2002).

A. Osborne, H. Zhang, W. Yang, E. Seto, and G. Blanck. Histone deacetylase activity represses gamma-interferon inducible HLA-DR gene expression following the establishment of a DNase I-hypersensitive chromatin conformation. Molecular and Cellular Biology 21(19): 6495-6506 (2001).