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Michael D. Cole, Ph.D.

Contact Information:

Professional Interests:

Molecular basis of cancer; transcription factors; mechanisms of chromosome-mediated transcriptional control; target genes for oncogenic pathways.

Dr. Cole received a B.A. in physics from Ohio Northern University in 1973 and a Ph.D. in biophysics in 1978 from Johns Hopkins University. Following postdoctoral work in the Biology Department at Johns Hopkins, Dr. Cole joined the faculty of the Department of Biochemistry at the St. Louis University Medical School in 1980. In 1984, he moved to the faculty of the Department of Molecular Biology at Princeton University. Dr. Cole joined the faculty of the Department of Pharmacology and Toxicology in the Dartmouth Medical School in 2003.

Studies of the genetic events involved in the induction of cancer provide an opportunity to define the molecular basis of the disease and to study the regulation and function of important eukaryotic genes that control cell proliferation. The c-myc gene encodes a transcription factor that is critical for progression through the cell cycle, and mutations that misregulate c-myc are frequently found in human and animal cancers. Dr. Cole's central research interest is to define the cellular target genes through which c-myc and other oncogenic transcription factors function and also to identify the nuclear factors that mediate target gene regulation.

TRRAP (Transformation/transactivation domain associated protein) was discovered as a nuclear cofactor that is essential for the oncogenic activity of c-Myc and E2F. TRRAP is a component of both the SAGA and TIP60/Nu4A chromatin remodeling complexes, where it is associated with the histone acetyltransferases GCN5 and TIP60/Esa1. This finding indicates that one function of c-Myc is to recruit chromatin modifying complexes to specific target sites. Recent studies show that the C-terminal domain of TRRAP that is related to ATM is required for the recruitment of histone acetyltransferase activity. However, since both the huge size (3750-3850 amino acids) and primary sequence of TRRAP protein are highly conserved in evolution, it suggests that TRRAP has an intrinsic function beyond any role as a scaffold in these complexes. Dr. Cole is exploring the function of TRRAP and its role in oncogenic transformation through biochemical purification of complexes and the molecular biology of TRRAP-associated proteins.

By expanding on an analysis of the c-Myc protein through affinity chromatography, two new nuclear cofactors called TIP49 and TIP48 were identified. These cofactors have highly conserved ATPase/helicase motifs, and it was established that the TIP49 ATPase is essential for Myc and E2F oncogenic function. Further analysis of these complexes revealed that they contained two additional actin-related proteins, BAF53 and ß-actin itself. Targeted mutations in BAF53 inhibit oncogenic transformation by c-Myc. Interestingly, the TIP complex appears to modulate the apoptotic activity of c-Myc, whereas the TRRAP complex does not. Ongoing studies of TIP49/TIP48 parallel those of TRRAP, using both biochemical and genetic approaches to investigate the function of these highly conserved nuclear factors.

A second project involves the analysis of cell lines devoid of Myc function due to targeted gene knockout. These cells showed that many previously proposed target genes of the c-Myc transcription factor were not misregulated in log phase cells, even though the myc knockout cells exhibit a stable, very slow growth phenotype. These studies indicate that as yet undefined targets must be responsible for the effect of c-Myc on the cell cycle and hence presumably on tumor cell growth. A functional complementation screen was developed to isolate cDNAs from complex libraries that can rescue the slow growth phenotype of Myc-deficient cells. In the initial studies, every fast growing cell had acquired a myc cDNA from the library, indicating that the Myc pathway is unique and not readily bypassed by other cellular factors. By eliminating myc cDNAs from the library and repeating the screen, the serine hydroxymethyltransferase genes were identified as critical and direct c-Myc target genes involved in growth control. Ongoing studies are aimed at identifying additional Myc target genes through functional complementation.

Courses Taught:

Pharmacology 129. Principles of Receptor Action - Co-Course Director