James F. Williams

Professor

Education

Ph.D., University of Toronto
Postdoctoral Appointment, University of California, Berkeley

Research

The human adenovirus system has proved to be a powerful model for analyzing the factors responsible for the development of cancer cells from normal cells, but although most, if not all, of the 49 known human adenovirus serotypes transform rodent cells in vitro, only a few of them actually cause tumor formation in rodents. Group A serotypes are, for example, highly oncogenic in rats, while those of group C fail to induce tumors.

Work carried out by ourselves and others has shown that the gene products required and apparently sufficient for the oncogenic transformation of rodent cells are encoded by the early transcriptional units E1A and E1B, located in the left-hand 11% of the viral genome. This region has a complex organization, and more than six proteins, encoded by two sets of overlapping messages, map within it. We are using various genetic and molecular approaches to define the requirements for these adenoviral early gene products in the initiation and maintenance of oncogenic transformation in rodent cells and to analyze the role(s) of the product(s) that determine the striking differences in viral oncogenicity observed between group A (serotype 12) and group C (serotype 5) viruses.

Recently we have developed a novel approach to help define the basis for the capacity of Ad12 to induce tumors with high efficiency in rodents and the inability of Ad5 to do so. We have constructed type 12/type 5 adenovirus chimeric E1A genes and have used these to identify an oncogenic determinant of Ad12, which comprises a unique 60 base pair segment contiguous with and separating conserved regions 2 and 3 in the gene. A similar but slightly larger segment is present in this location in the E1A gene of highly oncogenic simian adenovirus type 7, but significantly it is missing completely from the E1A gene of Ad5, which is nononcogenic. Confirmation that this unique spacer segment in Ad12 is required for oncogenesis has been obtained by phenotypic analysis of mutants carrying point mutations introduced into that region. Currently we are applying the chimeric approach to analysis of the potential role of the second exon region of E1A in tumor induction and over the next few years our efforts will focus on further genetic analysis of these and other potential oncogenic determinants, and upon extended functional analysis of E1A and E1B gene products.

Publications

Williams J, Williams M, Liu C, Telling G. Assessing the role of E1A in the differential oncogenicity of group A and group C human adenoviruses. Current Topics in Microbiological Immunology, 199/III:149-175, 1995.

Telling GC, Williams J. Constructing chimeric type 12/type 5 adenovirus E1A genes and using them to identify an oncogenic determinant of adenovirus type 12. Journal of Virology, 68:877-887, 1994.

Telling, GC, Perera S, Szatkowski-Ozers M, Williams J. Absence of an essential regulatory influence of the adenovirus E1B 19-kilodalton protein on viral growth and early gene expression in human diploid WI38, HeLa, and A549 cells. Journal of Virology, 68:541-547, 1994.

Telling GC, Williams J. The E1B 19-kilodalton protein is not essential for transformation of rodent cells in vitro by adenovirus type 5. Journal of Virology, 67:1600-1611, 1993.

Lamberti C, Williams J. Differential requirement for adenovirus type 12 E1A gene products in oncogenic transformation. Journal of Virology, 64:4997-5007, 1990.