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| In the laboratories of Huntsman Cancer Institute (HCI), researchers study the mechanisms of genes and their functions to discover possible methods of preventing, circumventing, or even reversing the changes that cause cancer. Each year, hundreds of articles by HCI investigators appear in peer-reviewed journals; here are three important highlights from 2005.
A dimmer switch for genes. Protein molecules have some regions with definite, fixed structures and others more randomly organized. Graves Lab researchers discovered that the randomly structured regions—formerly thought to serve only minor roles in the function of genes—are important in turning genes on and off when modified. HCI investigator Barbara Graves, PhD, professor and chair of the Department of Oncological Sciences, along with other Graves Lab researchers and scientists from the Universities of British Columbia and Toronto, studied Ets-1, a protein that binds to genes to help read genetic information that controls cell functions and is associated with several types of cancer. They added phosphates to an unstructured region of the protein and found that as each phosphate was added, the ability of the protein to bind gradually decreased. Previously, the effect of adding phosphates had been described as a sharp on/off switch. Because any protein has the potential to be organized with structured and unstructured regions that work together, these findings have broad implications for the study of all proteins. Pufall MA, Lee GM, Nelson ML, Kang HS, Velyvis
A, Kay LE, McIntosh LP, Graves BJ. Variable control of Ets-1 DNA
binding by multiple phosphates in an unstructured region.
A mechanism to control gene activation. From the Cairns Lab, researchers reported the discovery of a special type of molecular structure: a nucleosome bearing a protein called Htz1. This nucleosome attaches to genes and keeps them properly turned off until it is ejected in a regulated manner to help turn the genes on. “Discoveries like this help us begin to understand how gene activation and repression is altered in cancer cells, and how that leads to tumor growth,” says Brad Cairns, PhD, associate professor of oncological sciences and lead scientist on the study. “However, designing targeted treatments to correct these alterations requires deep knowledge of basic cellular mechanisms that regulate gene expression.” Zhang H, Roberts DN, Cairns BR. Genome-wide
dynamics of Htz1, a histone H2A
More about APC. Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene cause 85 percent of noninherited colon cancers. In 2004, scientists in the Jones Lab at HCI published results showing that APC controls the conversion of dietary vitamin A into retinoic acid (RA). If that process is impaired by mutation, cells in the intestinal lining cannot develop properly and colon cancer may result. The study raised the possibility that many colon cancers could be prevented by using drugs to restore retinoid activity. During 2005, Jones Lab scientists continued to define the factors that control the process, finding that APC regulates expression of rdh11, a retinol dehydrogenase enzyme, to control RA production. “As we refine our understanding, the concept of using retinoids as a form of chemoprevention to keep colon cells from becoming cancerous appears even more viable than before,” says David Jones, PhD, associate professor of oncological sciences and lead investigator on the study. Nadauld LD, Sandoval IT, Chidester S, Yost
HJ, Jones DA. Adenomatous polyposis
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