UMC - Department of Biochemistry

What's happening in the Department?

December, 2006: The Raucher group recently received funding from the National Cancer Institute of NIH for cancer research.

Congratulations to Drazen Raucher, Ph.D, Department of Biochemistry! Dr. Raucher received funding from the National Cancer Institute of NIH for his cancer research. Current treatment of solid tumors is limited by inherent tumor resistance to radiation or chemotherapy and toxicity from systemic administration of antineoplastic agents. The ultimate goal of his research is to overcome these limitations by developing a targeted therapeutic approach for localized tumors that increases the specificity and efficacy of the therapy and reduces the cytotoxicity in normal tissues.
His team has developed a thermally responsive polypeptide which inhibits c-Myc transcriptional activity and proliferation of cells in culture. Their hypothesis is that after systemic administration, genetically engineered polypeptides can be targeted to the tumor site by applying local hyperthermia. This will result in accumulation of the agent in the tumor with subsequent inhibition of tumor growth. These studies will provide the basis for a new technology for targeted delivery of specific oncogene inhibitors. Specific targeting of the proposed therapeutic polypeptides to solid tumors by local hyperthermia would increase specificity and efficacy of treatment and reduce the cytotoxicity in normal tissues. Thus, development of the proposed polypeptide-mediated therapeutic delivery system would provide an alternative means to effectively substitute or augment present therapy for treatment of localized tumors. The successful completion of the proposed research will provide In vivo data to move this therapy towards the translational stage of human therapeutics.

September, 2003: The Hebert group had recently been awarded a grant from the Muscular Dystrophy Association to study the protein that causes the neurodegenerative disease Spinal Muscular Atrophy (SMA). SMA is the leading genetic cause of infant mortality, and most patients with this disease have mutations in the survival motor neurons gene, SMN1. Normally, the SMN protein plays a crucial role in the biogenesis of pre-mRNA splicing factors. Consequently, patients with SMA display motor neuron death, presumably because motor neurons are extremely vulnerable to the reduction of splicing factors.

The goal of our project is to better understand the RNA processing machinery, which is effected in patients with SMA. We will do this by investigating the protein dynamics found with a subnuclear domain termed the Cajal body. Cajal bodies are known to contain factors that are neccesary for the maturation of RNA splicing factors. Interestingly, SMN shows localization within Cajal bodies, but it's function within this domain remains elusive. We have recently found that SMN and the marker protein for Cajal bodies, coilin, interact. Furthermore, the association between coilin and SMN is neccesary for SMN to accumulate in the Cajal body. Considering that SMA is a very tissue-specific disease (effecting primary motor neurons) and that Cajal bodies are prominent in this cell type, it is possible that the SMN/coilin interaction represents an important step in splicing factor biogenesis. Therefore, we are currently isolating proteins that regulate the interaction between coilin and SMN. It is our hypothesis that this work will identify targets for therapy that functionally increase SMN levels and lessen the severity of SMA.

Strategy for the isolation of coilin associated proteins(CAPs) from yeast three-hybrid screen. (A)Constructs used for the Yeast three-hybrid screen. Coilin (or fragments thereof) will be cloned into pBridge such that a fusion with the GAL4 binding domain is generated. SMN will be cloned into a seperate site in pBridge such that the expression of SMN is under the control of a methionine sensitive promotor. The pBridge vetor will be transformed into yeast. This yeast strain will then be conjugated to yeast which have been pretransformed with a brain cDNA library cloned into an activation domain vector (such as pGaDT7) (B) Scheme for the isolation of CAP proteins whose regulation with coilin is altered by SMN. In the absence of SMN expression, the CAP protein X interacts with coilin resulting in teh transcription of various reporter genes. A decrease in reporter gene activity upon the expression of SMN indicates that the interaction between coilin and CAP X is afected.

January, 2001: The Chaires' group and collaborators have succeeded in creating molecules that selectively recognize different conformations of DNA. Moreover, these compounds have the capability of interconverting B-DNA, the right-handed conformer, and Z-DNA, the left-handed conformer. The discovery of these compounds has significant implications for the design of new anticancer drugs. For a brief account of this work from Scientific American, go to http://www.sciam.com/news/101000/1.html.