Primary Appointment:
 Microbiology & Immunology

GEBS Cluster Affiliations:
 Biochemistry, Molecular Biology, & Genetics - BMBG
 Immunology, Microbiology, and Vaccine Biology - IMV

University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 672
Rochester, New York 14642

Phone: (716) 275-0101
E-Mail: DJMC@UHURA.CC.ROCHESTER.EDU

Molecular Pathogenesis of Human Papillomaviruses.

Cervical cancer is the most common cancer-related cause of death worldwide, and infection with human papillomavirus (HPV) types 16 and 18 play a role in the etiology. My laboratory is interested in studying early region onco-proteins of HPV 16, namely E6, E7 and E5, and two other proteins E1 and E2, which appear to be involved in the replication of the HPV genome. The papillomaviruses are attempting to replicate in terminally differentiating cells, so for it’s own propagation, it needs to stimulate cells into S-phase in order to utilize the cells' replicative machinery. My laboratory is particularly interested in the cellular signals for keratinocyte differentiation and how the HPV proteins impact on these pathways to induce cells to move into S-phase for viral DNA replication.

Interaction of HPV 16 E7 oncoprotein with cellular factors: In vivo infection with the oncogenic types 16 and 18 causes inhibition of differentiation of the epithelium, resulting in a premalignant lesion. Two early genes, E6 and E7, are sufficient to immortalize and inhibit differentiation of human keratinocytes. The two early genes interact with two cellular factors, p53 and the retinoblastoma gene product (Rb). E6 binds p53 and degrades it through the ubiquitin pathway, while E7 binds Rb. We have recently shown that Rb can bind to the AP-1 family of transcription factors and activate transcription from an AP-1 regulated promoter. This may be an important since the AP-1 factors have been known for some time to be up-regulated during differentiation.

The retinoblastoma protein (Rb) represses the activity of members of the E2F family of transcription factors. The mechanism of inhibition is unclear, but recently in collaboration with Dr. Tony Kouzarides’ laboratory at University of Cambridge, UK, we showed that Rb binds to the histone decaetylase proteins, HDAC-1/2. Histone deacetylases remove acetyl groups from lysines contained in the tails of histone proteins, resulting in chromatin condensation and repression of transcription. Therefore, the ability of Rb to interact with deacetylase activity may be an important property for the repression of E2F. The HPV-16 E7 protein, which binds to Rb, has been shown to abrogate the repressive activity of Rb for E2F, resulting in free E2F and transcriptional activation. Future research will determine the relationships between E7, Rb and HDAC-1 and the biological effects resulting from these interactions.

HPV-16 E6 and interaction with cellular proteins: The E6 protein binds in a trimeric complex with the cellular protein E6AP and p53. The result is the ubiquitination of p53 and the subsequent proteolysis of the protein. We have recently found that HPV-16 E6 also binds to a cellular co-activator of transcription. The biological consequences of this interaction are currently under investigation.

HPV-16 E5 and interaction with EGF receptor: The E5 ORF of the HPVs encodes a short hydrophobic peptide, structurally similar to BPV-1 E5, but of unknown function. To investigate the function of the HPV E5 ORF, we have expressed the protein in keratinocytes. Enhanced cell growth was observed, particularly in the presence of epidermal growth factor (EGF). This appears to be due to the fact that HPV 16 E5 alters the turnover rate of the EGF receptor in cells, thereby increasing the number of cell surface EGF receptors. It appears to acheive this through an indirect effect, since E5 expressed in yeast affects the function of the vacuolar ATPase, which is involved in receptor recycling. The use of the yeast system will allow structure/function analysis and help elucidate how E5 alters the ATPase function.

A more detailed description of this laboratory's research is available.
In addition, a McCance Lab web site is also available.

Nead, M.A., Baglia, L.A., Antinore, MJ., Ludlow, J., McCance, D.J. (1998) RB binds c-Jun and activates transcription. EMBO Journal 17:2342-2352.

Sun, Y-N., Han, H., McCance, DJ. (1998) Active domains of HPV-11 E1 protein for origin replication. J. Gen. Virol. 79: 1651-1658.

For an up-to-date review see a new book from American Society for Microbiology:
Human Tumor Viruses. Ed. Dennis J. McCance. Chapters: 6 and 7. ASM Press. 1998.