Our Science – Wiest Website

Jonathan S. Wiest, Ph.D.

Laboratory of Cancer Biology and Genetics Adjunct Investigator National Cancer Institute 31 Center Drive, Room 4A48 (Office) 37 Convent Drive, Room 4054 (Lab) Bethesda, MD 20892 Phone:   301-451-9638 Fax:   301-451-6238 E-Mail:   wiestj@mail.nih.gov

Biography

Dr. Jonathan S. Wiest obtained his bachelors degree in analytical chemistry from the University of Wisconsin-Milwaukee in 1980. He worked as a production chemist synthesizing oligonucleotides for P-L Biochemicals until he began graduate school in 1982 at the Medical College of Ohio in Toledo. Dr. Wiest received his Ph.D. in Biochemistry in 1988 and then did a Postdoctoral fellowship at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. He rose to the rank of Senior Staff Fellow and then assisted in establishing a Cancer Research Institute in western Colorado. In 1996 he became an assistant professor at the University of Cincinnati, Department of Environmental Health, School of Medicine. Dr. Wiest joined the Center for Cancer Research at the National Cancer Institute as the Associate Director for Training and Education in November of 2001. In 2003, Dr. Wiest received the NIH Director’s award for Mentoring as well as the NCI Outstanding Mentor award. The major focus of his research involves genetic alterations in lung tumorigenesis. He is involved in studies to identify tumor suppressor genes and altered signaling pathways in lung cancer. He is the author or co-author of over thirty journal articles and book chapters.

Research

Lung cancer is the leading cause of cancer-related mortality in both men and women and remains a major health issue. More than 170,000 individuals will die from lung cancer in the coming year, more than breast, prostate and colon cancer combined. The majority of lung cancer cases is attributable to tobacco smoking and in some cases other environmental risk factors. Although the relative risk of developing lung cancer declines dramatically in smokers who quit, former smokers remain at risk for the disease. Several recent studies show that greater than 50% of newly diagnosed lung cancers occur in former smokers. Of the tumors detected in former smokers, nearly 50% occurred in patients who had quit for more than five years. It is estimated that there are approximately equal numbers of smokers and former smokers in the United States. Since smoking cessation is a major public health initiative, former smokers will increasingly account for a higher percentage of lung cancer cases. Thus, two high-risk population groups exist for lung cancer and improved disease management can be beneficial to both current and former smokers. Additionally the prognosis for lung cancer patients is very poor, and is due, in part, to the historical lack of effective early detection measures.

TUMOR SUPPRESSOR GENES (TSG) ON CHROMOSOME 9P:
Chromosome 9p deletions and alterations occur early and often in lung cancer. The p16/CDKN2 locus, located on 9p, is suspected to be the major tumor suppressor gene inactivated in this tumor type. However, we identified a region of homozygous deletion on the short arm of chromosome 9p. We proposed that the region harbors a TSG important in lung tumorigenesis. We furthered our analysis with 30 non-small cell lung cancer and 12 small cell lung cancer cell lines by screening them with 55 markers to identify new regions of homozygous deletion on chromosome 9p. Three novel non-contiguous homozygously deleted regions were detected and ranged in size from 840 Kb to 7.4 Mb. One of these regions led to the identification of a gene identified as TUSC1. Multiplex PCR and Southern blot confirmed the homozygous deletion of TUSC1. Northern blot analysis of TUSC1 demonstrated two transcripts of approximately 2 and 1.5 kb that are likely generated by alternative polyadenylation signals. Both transcripts are expressed in several human tissues and share an open reading frame encoding a peptide of 209 amino acids. Analyzing lung cancer cell lines for RNA and protein expression demonstrated down regulation of TUSC1 in several cell lines suggesting TUSC1 may play a role in tumorigenesis. DNA sequencing of the TUSC1 gene open reading frame detected missense mutations in 7 of 41 cell lines examined and we are currently analyzing matched tumor and normal lung cancer samples to determine if somatic mutations occur in TUSC1. Studies using lung tumor cell lines stably transfected with TUSC1 show reduced proliferation both in vitro and in vivo. Taken together, these data suggest that chromosome 9p may contain other tumor suppressor genes important in lung tumorigenesis and that TUSC1 may be a candidate TSG. Current studies will examine how induction of TUSC1 expression will alter the phenotype of cells in culture.

THE MAP3K8 GENE IN LUNG TUMORIGENESIS:
The MAP3K8 gene is a MAP kinase kinase kinase expressed in a variety of cells and found to be oncogenic and constitutively activated when altered at the 3’ end. However, mutation of the gene appears to be a rare event in humans, but altered MAP3K8 expression is associated with multiple tumor types. MAP3K8 possesses the unique characteristic of activating multiple cascades, including both proliferative and apoptotic signal transduction pathways such as the MEK-1 and SEK-1 pathways, respectively. In NIH3T3 transfection assays utilizing lung tumor DNA, our lab identified a 3’ alteration of MAP3K8 similar to the previous reports. We first hypothesized that MAP3K8 might be a target for mutation since we were the first group to report an activating mutation in a primary human tumor. However, it has become clear that mutations are not a common event in tumorigenesis for this gene. Subsequently we showed varied levels of expression of the gene in lung tumor cell lines. This led us to investigate other downstream pathways that could explain the tumorigenic potential of MAP3K8. These included transcription factor array analysis and protein kinase array experiments. We were able to confirm other reports in the literature demonstrating upregulation of NF-kappaB and AP-1 as well as identify other important transcription factors not reported in the literature. These and other experiments, as well as published reports led us to modify our hypothesis that increased expression of MAP3K8 occurs in lung cancer and contributes to disease progression. Real-time PCR demonstrated 7/17 non-small cell lung cancer (NSCLC) cell lines significantly increased MAP3K8 mRNA expression, with 3 cell lines over 50-fold greater that of normal lung cells. While 4/14 small cell lung cancer (SCLC) cell lines increased expression, the majority of SCLC cell lines decreased expression. We have recently shown that increased protein expression of MAP3K8 in these cell lines leads to hyperphosphorylation of its downstream target MEK-1. These data suggest MAP3K8 expression is altered in lung cancer cells lines and because of its role in the inflammatory response, MAP3K8 overexpression may be involved in tumor progression.

This page was last updated on 9/12/2008.