SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

More documents

Recommendations

Info

V I R A L O N C O L O G Y P R O G R A M Obuchi, M, Fernandez, M, and Barber, GN. Development of recombinant vesicular stomatitis viruses that exploit defects in host defense to augment specific oncolytic activity. Journal of Virology 77:8843-56, 2003. Ghosh, SK, Wood, C, Boise, LH, Mian, AM, Deyev, VV, Feuer, G, Toomey, NL, Shank, NC, Cabral, L, Barber, GN, and Harrington, WJ Jr. Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NFkappa B. Blood 101:2321-7, 2003. Balachandran, S and Barber, GN. Defective translational control facilitates vesicular stomatitis virus oncolysis. Cancer Cell 5:51-65, 2003. Poroniscu, M, Mian, A, and Barber, GN. The oncolytic effect of recombinant vesicular stomatitis virus is enhanced by expression of the fusion cytosine deaminase/uracil phosphoribosyltransferease suicide gene. Cancer Research 63:8366-76, 2003. HIGHLIGHTS/DISCOVERIES • Discovered that IFN-inducible protein kinase PKR is a critical mediator of innate immunity to a number of viruses, since mice lacking this kinase are very susceptible to lethal infection by several viruses at doses that are innocuous to wild type mice. • Discovered that VSV has potent oncolytic (antitumor) properties. Dr. Barber’s laboratory has shown that VSV replicates to high levels in tumorigenic, but not normal cells, and has identified defects in IFN signaling and translational control in tumorigenic cells as possible reasons for this uncontrolled replication. • Developed recombinant VSV that expresses other virus proteins, such as from HCV and HPV (implicated in tumorigenesis), as possible vaccines for these viruses. • Constructed VSV variants expressing suicide cassettes and immunomodulatory genes in an effort to increase the potency and specificity of VSV oncolysis. PAUL E. BOEHMER, PH. D. Associate Professor of Biochemistry and Molecular Biology DESCRIPTION OF RESEARCH Researchers in Dr. Boehmer’s laboratory are studying molecular mechanisms of replication and recombination in herpes simplex virus type-1 (HSV-1). HSV-1 serves as an excellent system in which to study DNA transactions. Hence, like eukaryotic chromosomes, the HSV-1 genome contains multiple origins of replication. Replication of the HSV-1 genome is mediated by the concerted action of several virus-encoded proteins that are thought to assemble into a multiprotein complex. Several host-encoded factors have also been implicated in viral DNA replication. Furthermore, replication of the HSV-1 genome is known to be closely associated with homologous recombination, which may function in the initiation of DNA replication and in maintaining genome stability. Moreover, the virusencoded enzymes also provide a system in which to investigate the interaction of DNA replication enzymes with DNA damage. HSV-1 also is the prototypic herpes virus and therefore serves as a model to understand the mechanism of replication of this class of virus. In this regard, HSV-1 is one of eight human herpes viruses that are known to cause diverse diseases ranging from cold sores and chicken pox to mononucleosis and even cancer. The high incidence of herpes viruses in the human population and the increased susceptibility of immunocompromised individuals to these viruses make them a very important public health problem. HSV-1 in particular is the cause of oro-labial lesions as well as more serious encephalitis and corneal blindness. Most recently, Dr. Boehmer’s laboratory has proposed to examine how the virus initiates replication at an origin, the role recombination plays during initiation and at later times during the replicative cycle, how leading and lagging strand DNA synthesis are coordinated at the viral replication fork, and finally, the mechanism whereby UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 135
V I R A L O N C O L O G Y P R O G R A M the viral DNA polymerase can promote translesion DNA synthesis. Collectively, the proposed studies will provide novel insight into the replication of this medically important and biologically fascinating virus. They also will serve to increase the overall knowledge of fundamental mechanisms in DNA replication and recombination. SELECTED PUBLICATIONS 2002 Tanguy Le Gac, N and Boehmer, PE. Activation of the herpes simplex virus type-1 origin-binding protein (UL9) by heat shock proteins. Journal of Biological Chemistry 277:5660-6, 2002. Nimonkar, AV and Boehmer, PE. In vitro strand exchange promoted by the herpes simplex virus type-1 single strand DNA-binding protein (ICP8) and DNA helicase-primase. Journal of Biological Chemistry 277:15182-9, 2002. Villani, G, Tanguy Le Gac, N, Wasungu, L, Burnouf, D, Fuchs, RP, and Boehmer, PE. Effect of manganese on in vitro replication of damaged DNA catalyzed by the herpes simplex virus type- 1 DNA polymerase. Nucleic Acids Research 30:3323-32, 2002. 2003 Boehmer, PE and Nimonkar, AV. Herpes virus replication. IUBMB Life 55:13-22, 2003. Nimonkar, AV and Boehmer, PE. The herpes simplex virus type-1 single-strand DNA-binding protein (ICP8) promotes strand invasion. Journal of Biological Chemistry 278:9678-82, 2003. Nimonkar, AV and Boehmer, PE. On the mechanism of strand assimilation by the herpes simplex virus type-1 single-strand DNA-binding protein (ICP8). Nucleic Acids Research 31:5275-81, 2003. Nimonkar, AV and Boehmer, PE. Reconstitution of recombination-dependent DNA synthesis in herpes simplex virus 1. Proceedings of the National Academy of Sciences USA 100:10201-6, 2003. Boehmer, PE and Villani, G. Herpes simplex virus type-1: a model for genome transactions. Progress in Nucleic Acid Research and Molecular Biology 75:139-171, 2003. HIGHLIGHTS/DISCOVERIES • Discovered that recombination reactions were promoted by the HSV single-strand DNA binding protein. • Reconstituted recombination-dependent DNA synthesis in a eukaryotic viral system. • Discovered that cellular heat shock proteins participate in the initiation of viral origin-specific replication. • Discovered translesion synthesis by a model eukaryotic replicative DNA polymerase. LAWRENCE H. BOISE, PH.D. Associate Professor of Microbiology and Immunology DESCRIPTION OF RESEARCH Regulation of Programmed Cell Death Programmed cell death, or apoptosis, is a process utilized by multicellular organisms to eliminate unnecessary or damaged cells without inducing an inflammatory response. The ability of inducing a cellular suicide is required for normal development and maintenance of cell number in multicellular organisms since loss of control of this process can lead to cancer, autoimmune disease, or neurodegenerative disorders in mice and humans. While the genetic studies in the nematode suggest that members of the Bcl-2 family should function upstream of caspases, this result could be the consequence of two biochemical explanations—either Bcl-2 blocks caspase activation or Bcl-2 blocks the consequence of protease activation. In studies performed on a pro-B cell line, Dr. Boise and his colleagues have found cooperativity between overexpression of Bcl-2 family members and inhibition of caspases in the 136 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
Page 1 and 2:
S C I E N T I F I C R E P O R T 2 0
Page 3 and 4:
I N T R O D U C T I O N A N D P R O
Page 5 and 6:
Page 7 and 8:
Page 9 and 10:
Page 11 and 12:
L E A D E R S H I P MULTIDISCIPLINA
Page 13 and 14:
L E A D E R S H I P EXTERNAL ADVISO
Page 15 and 16:
C A N C E R P R E V E N T I O N A N
Page 17 and 18:
Page 19 and 20:
Page 21 and 22:
Page 23 and 24:
Page 25 and 26:
Page 27 and 28:
Page 29 and 30:
Page 31 and 32:
Page 33 and 34:
Page 35 and 36:
Page 37 and 38:
Page 39 and 40:
Page 41 and 42:
Page 43 and 44:
Page 45 and 46:
Page 47 and 48:
C L I N I C A L O N C O L O G Y R E
Page 49 and 50:
Page 51 and 52:
Page 53 and 54:
Page 55 and 56:
Page 57 and 58:
Page 59 and 60:
Page 61 and 62:
Page 63 and 64:
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
T U M O R C E L L B I O L O G Y P R
Page 81 and 82:
Page 83 and 84:
Page 85 and 86:
Page 87 and 88:
Page 89 and 90:
Page 91 and 92:
Page 93 and 94:
Page 95 and 96:
Page 97 and 98: T U M O R C E L L B I O L O G Y P R
Page 117 and 118: T U M O R I M M U N O L O G Y P R O
Page 143 and 144: V I R A L O N C O L O G Y P R O G R
Page 147: V I R A L O N C O L O G Y P R O G R
Page 157 and 158: S H A R E D R E S O U R C E S 3) La
Page 159 and 160: S H A R E D R E S O U R C E S C E L
Page 161 and 162: S H A R E D R E S O U R C E S D N A
Page 163 and 164: S H A R E D R E S O U R C E S G E N
Page 165 and 166: S H A R E D R E S O U R C E S I N F
Page 167 and 168: S H A R E D R E S O U R C E S P O P
Page 169 and 170: P U B L I C A T I O N S 2 0 0 2 - 2
Page 199 and 200:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 201 and 202:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 203 and 204:
P U B L I C A T I O N S 2 0 0 2 - 2
Page 205 and 206:
G L O S S A R Y IFN—interferon IL
show all

SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

Create successful ePaper yourself

Delete template?

Save as template?