MAJOR RESEARCH ADVANCES

 

Over time, William Dove and his colleagues have contributed in a series of distinct areas of genetics and biology. The unifying theme that connects his five decades of research in the McArdle Laboratory for Cancer Research is the regulation of growth. This theme is illustrated by the discovery of a series of elements of growth control - from DNA replication of phage lambda, through nuclear cycling in Physarum polycephalum, to neoplasia in the intestinal epithelium of mammals:

1) Trans-acting positive factors and a cis-acting replication origin of phage lambda, intrinsically activated by local transcription (Dove et al., 1969 and 1971; Furth et al., 1978; and Furth et al., 1979).

2) Periodic transcription for regulators of the cell cycle (Laffler et al., 1981 and Schedl et al., 1984b).

3) Feedback limitation of growth by differentiation (Bailey et al, 1992; Moser et al, 1992; Kaiser et al, 2007; Kwong et al, 2008)

4) Autonomous and non-autonomous negative regulators controlling homeostasis in the intestinal epithelium, identified by the Min, Mom1, and p53 alleles of the mouse and the Pirc allele of the rat (Moser et al., 1990; Su et al., 1992; Dietrich et al., 1993; Gould and Dove, 1997; Cormier et al., 1997; Halberg et al, 2000; and Amos-Landgraf, Kwong et al., 2007).

5) Strong synergy between complementary modifying factors, each with a mild effect on the growth of a tumor (Cormier and Dove, 2000).

6) Polyclonal interactions in the establishment of intestinal neoplasms (Merritt et al., 1997; Thliveris and Halberg et al., 2005; Thliveris et al., 2011).
7) Early longitudinal studies of the role of replication control in the formation of stable proliferative states of the host after infection by the temperate phage lambda (Ohasha and Dove, 1976). A general strategy to monitor colonic tumor development longitudinally in living animals (Pickhardt, Halberg, et al., 2005; Durkee et al., 2009; Irving et al, 2014A).

8) A genome-wide strategy for the discovery of protectors against cancer predispositions (Dove et al., 1998 and 2014).

9) The analysis of allelic ratios of both genomic DNAs and cDNAs from normal tissue and tumors, identifying both genetic and epigenetic routes to eliminating the function of the tumor suppressor gene Apc (Amos-Landgraf al., 2012).

10) Cental issues in public health related to colon cancer are being addressed in recent studies of the role of dietary supplementation by vitamin D (Irving et al, 2011 and 2014) and the association of serum markers with early colonic neoplasia (Ivancic et al, 2014).

These advances have rested on the development of new methods.

1) Efficient mutagenesis in Physarum polycephalum and the laboratory mouse, leading to the first extensive university-based program of phenotype-driven genetic analysis of the biological problems special to each of these two experimental organisms (Haugli and Dove, 1972; Schedl et al., 1984a; Shedlovsky et al., 1986; McDonald et al., 1990; and Vitaterna et al., 1994). The Min mouse, generated by germline mutagenesis by ENU (Moser et al., 1990) has provided a platform for genetic, cellular, and molecular studies of multiple intestinal neoplasia in hundreds of laboratories, worldwide. With his McArdle colleague Michael Gould he has now adapted germline ENU mutagenesis to the laboratory rat, obtaining a colon cancer kindred of this second laboratory genus(Amos-Landgraf, Kwong et al., 2007).

2) The molecular genetics of Physarum polycephalum, from Mendelian dissection of the gene families for the eukaryotic cytoskeleton to opening the molecular analysis of gene function in this organism by DNA transformation (Schedl and Dove, 1982 and Burland et al., 1993).

3) Nested sets, recombination and genetic structure:

a) The integrated lambda prophage (Franklin et al., 1965)

b) Regions of mammalian chromosomes over which strong positive interference operates (King et al., 1989)

c) The importance of somatic recombination in familial colon cancer (Haigis et al, 2002; Haigis and Dove, 2003; Kwong et al, 2007a; Amos-Landgraf et al., 2012)

Now, the laboratory concentrates on understanding the early colonic neoplasms - its three possible fates in patients and in our mouse and rat model. Learning molecular signatures associated with the likelihood to grow seeds collaborations with other laboratories developing analytic methods for the early detection of colon cancer.