The human papillomavirus (HPV) E2 protein is an important regulator of viral E6 and E7 gene expression. E2 can repress the viral promoter for E6 and E7 expression as well as block progression of the cell cycle in cancer cells harboring the DNA of "high-risk" HPV types. Although the phenomenon of E2-mediated growth arrest of HeLa cells and other HPV-positive cancer cells has been well documented, the specific mechanism by which E2 affects cellular proliferation has not yet been elucidated. Here, we show that bovine papillomavirus (BPV) E2-induced growth arrest of HeLa cells requires the repression of the E6 and E7 promoter. This repression is specific for E2TA and not E2TR, a BPV E2 variant that lacks the N-terminal transactivation domain. We demonstrate that expression of HPV16 E6 and E7 from a heterologous promoter that is not regulated by E2 rescues HeLa cells from E2-mediated growth arrest. Our data indicate that the pathway of E2-mediated growth arrest of HeLa cells requires repression of E6 and E7 expression through an activity specified by the transactivation domain of E2TA.The papillomaviruses are small DNA viruses that infect a variety of mammalian species, including humans. Human papillomavirus (HPV) infections are quite common and cause a variety of benign proliferations including cutaneous warts, venereal warts, genital squamous intraepithelial lesions, and orolaryngeal and -pharyngeal papillomas, as well as other types of hyperkeratoses (41). Certain HPV types have also been linked to specific malignant lesions, most notably cervical cancer and other anogenital cancers.Of the over 80 HPV types identified, approximately 30 HPV types are associated with genital tract lesions. Subsets of the anogenital HPV types are classified as either "low risk" or "high risk" depending upon the potential of the associated lesions to progress to cancer. HPV6 and HPV11 are low-risk HPV types that are associated with low-grade squamous epithelial lesions (venereal warts or condyloma accuminata), which rarely progress to cancer. HPV16, HPV18, and others are high-risk HPV types that are associated with intraepithelial neoplasias or squamous intraepithelial lesions that can progress to cancer (54).It is now evident that most cervical neoplasias, whether intraepithelial or invasive, can be attributed largely to HPV infection. The DNA of a high risk HPV type can be found in over 90% of human cervical cancers (54). In addition, transfection of high-risk HPV genomic DNA can extend the life span of primary human genital keratinocytes (the normal cellular host of HPVs) and can contribute to cellular immortalization (13,39,51). This ability of the high-risk HPV types to immortalize keratinocytes is not a property of low-risk HPV types (13, 39).Oncogenic viruses often exploit the machinery of the cells they infect in order to promote their own survival and replication. As a part of this process, they interfere with normal cellular control mechanisms, leading to abnormal cell growth, genetic alterations and even malignant transform...

To address elements that might uniquely characterize CD40 mediated signaling, the nuclear expression of three transcription factors was evaluated following B cell stimulation by CD40L and by anti-Ig antibody. Cross-linked CD40L was found to induce nuclear expression of NF-kappa B, AP-1 and NF-AT with a time course and intensity similar to that produced by anti-Ig. Examination of NF-kappa B in more detail demonstrated that the CD40 mediated expression of DNA binding complexes correlated with induction of trans-activating activity which again attained similar levels following cross-linking of CD40 and slg. Despite the marked similarity in transcription factor induction triggered through CD40 and slg, differences in the intracellular signaling pathways utilized were apparent in that protein kinase C (PKC) depletion did not affect CD40 mediated induction of NF-kappa B even as induction by anti-Ig was abolished. These results suggest that a 'final common pathway' or convergence of transcription factor induction may exist for two distinct receptors, each of which is individually capable of triggering cell cycle progression, despite the use of separate intracellular signaling pathways that differ at the level of PKC. Although transcription factor induction was similar for CD40L and anti-Ig early on, subtle differences in expressed NF-kappa B and AP-1 nucleoprotein complexes were apparent at 24 h. Such differences may play a role in determining the variant effects on B cells of stimulation through these two receptors.

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