Replication of HPVs is of two types. Maintenance replication occurs in basal cells of epithelium, and amplified replication only occurs in superficial layers of papillomas. Stopping maintenance replication would cure infected persons of HPV. Stopping amplified replication would eliminate spread of HPV. The premise of this proposal is that HPV replication is controlled, at least in part, by transcription factors which program differentiation of epithelial cells. Transcription factors control replication by binding at or near sites of initiation, or regulate transcription of proteins needed for replication. The hypothesis to be tested is that transcription factors belonging to the cEBPs family of transcription factors are part of the complex machinery that determines how HPVs replicate. cEBPs direct differentiation. cEBPs are expressed in papillomas and bind to the regulatory region of HPV11. Interleukin 6, which elevates cEBPbeta and cEBP6, is expressed in papillomas and induces proteins in differentiating cells.
Aims will: 1) Determine whether transcription and/or replication of HPV11 DNA can be modulated by dumbbell oligonucleotides to cEBP binding motifs. In vivo assays will use these nuclease resistant oligomers to compete binding of cEBPs to HPV11 DNA. 2) Determine whether HPV replication and/or transcription can be modulated by point mutations of cEBP binding sites in the HPV11 DNA. 3) Determine whether HPV11 transcription and /or replication respond to the levels of cEBPbeta. An expression vector for cEBPbeta or addition of interleukin 6 will be used to change cEBPbeta levels. 4) Identify proteins from undifferentiated and differentiated keratinocytes and papillomas, that interact with the putative cEBP recognition sites in HPV11.

Project Start
1997-07-01
Project End
1999-03-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
14
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Long Island Jewish Medical Center
Department
Type
DUNS #
City
New Hyde Park
State
NY
Country
United States
Zip Code
11040
Chow, Louise T; Broker, Thomas R; Steinberg, Bettie M (2010) The natural history of human papillomavirus infections of the mucosal epithelia. APMIS 118:422-49
Wu, Rong; Abramson, Allan L; Symons, Marc H et al. (2010) Pak1 and Pak2 are activated in recurrent respiratory papillomas, contributing to one pathway of Rac1-mediated COX-2 expression. Int J Cancer 127:2230-7
Wu, Rong; Coniglio, Salvatore J; Chan, Amanda et al. (2007) Up-regulation of Rac1 by epidermal growth factor mediates COX-2 expression in recurrent respiratory papillomas. Mol Med 13:143-50
Ralph Jr, Walter M; Liu, Kai; Auborn, Karen J (2006) CCAAT/enhancer-binding protein beta represses human papillomavirus 11 upstream regulatory region expression through a promoter-proximal YY1-binding site. J Gen Virol 87:51-9
Dackour, Raduwan; Carter, Timothy; Steinberg, Bettie M (2005) Phosphatidylinositol 3-kinase regulates early differentiation in human laryngeal keratinocytes. In Vitro Cell Dev Biol Anim 41:111-7
Shikowitz, Mark J; Abramson, Allan L; Steinberg, Bettie M et al. (2005) Clinical trial of photodynamic therapy with meso-tetra (hydroxyphenyl) chlorin for respiratory papillomatosis. Arch Otolaryngol Head Neck Surg 131:99-105
Vambutas, A; DeVoti, J; Nouri, M et al. (2005) Therapeutic vaccination with papillomavirus E6 and E7 long peptides results in the control of both established virus-induced lesions and latently infected sites in a pre-clinical cottontail rabbit papillomavirus model. Vaccine 23:5271-80
Abramson, Allan L; Nouri, May; Mullooly, Virginia et al. (2004) Latent Human Papillomavirus infection is comparable in the larynx and trachea. J Med Virol 72:473-7
Vambutas, Andrea; Bonagura, Vincent R; Reed, Elaine F et al. (2004) Polymorphism of transporter associated with antigen presentation 1 as a potential determinant for severity of disease in recurrent respiratory papillomatosis caused by human papillomavirus types 6 and 11. J Infect Dis 189:871-9
Bonagura, Vincent R; Vambutas, Andrea; DeVoti, James A et al. (2004) HLA alleles, IFN-gamma responses to HPV-11 E6, and disease severity in patients with recurrent respiratory papillomatosis. Hum Immunol 65:773-82

Showing the most recent 10 out of 33 publications