Associate Professor
Ph.D., University of Texas

Adjunct Assistant Professor Ohio University, Department of Biological Science
Adjunct Assistant Professor The University of texas M.D. Anderson Cancer Center; Department of Experimental Radiation Oncology
Understanding genetic and molecular pathways of cancer and development

My research is focused on the p53 tumor suppressor pathway in cancer and development, in particular how p53 function is affected by genetic modifiers or DNA damage. The identification of risk modifiers of p53 as well as the essential players in its pathway will have important implications not only for the fundamental biology of cancer and development, but also for prevention, diagnosis, and therapy of malignant tumors.

Identifying modifiers of p53 tumorigenesis and development

My primary research interest focuses on the scientific understanding of what influences an individual’s risk of cancer. One hypothesis suggests that the risk of cancer is determined by the inheritance of cancer resistance or susceptibility genes, which are referred to as “genetic modifiers”. My goal is to identify these cancer-modifying genes. This avenue of research is difficult in humans due to the influences from the environment, another factor that may also increase a human’s risk of cancer. The use of mice as research subjects is an alternative to the use of humans because mouse research permits a more controlled environment for genetic studies. Through the process of inbreeding within each mouse line, we can produce a strain that is genetically identical; thus, particular cancer sensitivity or resistance genes can be maintained within the strain. Another advantage to using mice is the fact that the genes within a mouse line can be manipulated relatively easy.

The mouse model I use mimics cancer in humans through the deletion of the tumor suppressor gene, p53. This is a gene that is mutated in over 60% of all human tumors. The p53 gene functions to suppress the formation of tumors by turning on other genes that promote apoptosis, growth arrest, and DNA repair. Thus mutations in p53 would prevent the normal cellular functions from occurring thus leading to tumor formation. My scientific approach is to identify cancer modifying genes by first determining how tumors that form in mice due to the deletion of p53 change within the different strains of mice. Changes in tumorigenesis (i.e. tumor onset, tumor type, increased metastasis) are presumably a result of another gene that is altered within the mice. Analyzing genetic markers within the mouse tumor DNA can lead to the identification of these cancer-modifying genes. The discovery of these genes will help elucidate the genetic predisposition to cancer in humans and the genetic pathway of tumorigenesis. Understanding these pathways will aid in the design of new strategies for the diagnosis, prevention and treatment of the certain cancers.

In addition to modifiers of p53 that affect tumorigenesis, I have also uncovered a genetic modifier of p53 which results in embryonic lethality. Genetic modeling predicts that a recessive allele from an inbred strain of mice, CE/J, in combination with p53 heterozygosity or homozygosity , results in embryonic lethality.  Embryos isolated from mid to late gestation have abnormalities including neural tube defects, decreased size, and delayed development.  I am in the process of delineating the cause of these abnormalities , but initial experiments suggest that the smaller embryos have ceased to proliferate.  In addition, using a variety of different breeding strategies, I am mapping the chromosomal position of this modifier(s) of p53).  Once a region is determined, the gene will be cloned.

Determining the function and mechanism of hdm2 splicing .

Hdm2 , a downstream target of p53, binds and inhibits p53 transactivation.  Using immunohistochemistry to screen a panel of human tumors for HDM2, I detected high levels of HDM2 in the cytoplasm in 25% of lung tumors.  These samples contained full-length HDM2 and several alternate-splice forms of hdm2 mRNA.  Sequence analysis revealed deletions of the p53 binding domain and absence of a nuclear localization signal in the alternate-splice forms.  I have shown that one of the alternate splice forms, HDM2^ALT1 , binds and sequesters full-length HDM2 in the cytoplasm.  In addition, the binding of HDM2^ALT1 to full-length HDM2 prevented HDM2 from binding p53 and inhibiting p53 function (Evans et al, 2001).  Importantly, these altered hdm2   transcripts were made in normal and tumor cells when I exposed them to ultraviolet radiation, suggesting a novel mechanism of regulating p53 activity.  Since HDM2 binds and degrades p53, the disruption of the HDM2/p53 interaction by HDM2^ALT1 would lead to p53 stability and growth arrest.  To test this hypothesis and gain further insight into the mechanism by which DNA damage induces splicing of HDM2, I am using both tissue culture and transgenic mouse systems.

Evans, S.C ., Gu, J., Strong, L.C., Amos, C., and Lozano, G. A novel modifier of the tumor suppressor p53, mop1, results in embryonic lethality. Submitted.Evans, S.C., Liang, M., Gu, J., Strong, L.C., Amos, C., and Lozano, G. A novel modifier of the tumor suppressor p53, mop1, results in embryonic lethality. Mammalian Genome 15:1-9, 2004.

Iyer, R, Thames, HD, Tealer, J, Mason, K.A. and Evans, S.C. Effect of reduced EGFR function on the radiosensitivity and proliferative capacity of mouse jejunal crypt clonogens.  Radiotherapy and Oncology 72:283-289, 2004.

Malki A, Pulipaka A, Evans SC, and Bergmeier S. Structure-activity studies of quinoclidinone analogs as anti-proliferative agents in lung cancer cell lines.  Bioorg. Med. Chem. Lett. 16:1156-1159, 2006.    

Malki A, Gentry J and Evans SC. Differential effect of selected methylxanthine derivatives on radiosensitization of lung carcinoma cells. Exp Oncol. 28:16-24, 2006.

Ayanga B, Price R, Gu X, Lozano G, and Evans SC. Genetic mapping of a putative tumor suppressor locus that influences tumorigenesis and metastasis in mice.  Genes Chromosomes and Cancer, 45:668-675, 2006.

Dias CS, Liu Y, Yau A, Westrick L, and Evans SC. Alternative splicing of hdm2 to HDM2^ALT1 correlates with p53 stabilization after cellular stress. Cancer Research, 66:1-7, 2006.