My research is focused on the interactions between human papillomaviruses (HPVs) and their target cells. HPVs are small DNA tumor viruses that cause both benign and malignant tumors. The benign tumors, or papillomas, can be precursors to cancer. The HPVs cause essentially all cervical cancer and a subset of cancers in the head and neck. My research is primarily supported by a grant from the National Institute on Deafness and Communication Disorders to study recurrent respiratory papillomatosis (RRP), a disease caused by HPV infection of the larynx and other parts of the respiratory tract. We have found that several cellular signaling pathways associated with the EGF receptor are altered in activity in HPV-infected papilloma cells. We have also found that the papillomas are characterized by a slow rate of cell proliferation, and defects in differentiation. However, the cells are not triggered to die, as might be expected. We postulate that the altered signal transduction contributes to this phenotype. The specific studies in progress are:

1) HPV-induced alterations in signal transduction downstream of the EGF receptor (EGFR). Papilloma cells overexpress the EGF receptor, and show heightened responses to low levels of EGF compared to uninfected cells. In vivo, there is constitutive activation of MAPK. Papilloma tissues contain high levels of activated PI-3-Kinase, which is consistent with the activation of the EGFR since the EGFR activates PI-3-kinase. However, these tissues also contain high levels of the phosphatase PTEN. PTEN removes the phosphates on PIP3, which is phosphorylated by PI-3-Kinase. The competing activities of these two pathway intermediates results in lower than normal levels of activated AKT, the downstream effector of the PI-3-Kinase pathway. We have also found that activation of the second messenger STAT3 is reduced in papilloma tissues, and that PTEN can induce dephosphorylation of STAT3. Finally, we have found that NFkB activity is elevated in papillomas.
Studies are in progress to determine which viral protein(s) induce these changes in cell signaling, and permit survival in the face of reduced activity of Akt and STAT3. We are also determining the mechanism of the overexpression of PTEN. mRNA levels are higher in papilloma tissues, suggesting increased transcription. Preliminary studies with cultured HaCaT cells suggest that PTEN levels are regulated by activation of the PI-3-Kinase pathway. Finally, we are determining which altered signaling pathway, or combination of pathways, causes the defect in differentiation seen in the papillomas.

Recent publications related to these studies:
Johnston, D., Hall, H., DiLorenzo, T.P. and Steinberg, B.M. Elevation of the Epidermal Growth Factor Receptor and Dependent Signaling in Human Papillomavirus Infected Laryngeal Papillomas. Cancer Res. 59:968-974, 1999.

Zhang, P. and Steinberg, B.M. Overexpression of PTEN/MMAC1 and decreased activation of Akt in HPV-infected laryngeal papillomas. Cancer Res. 60:1457-1462, 2000.