Dr. Muchmore's interest in the functional role of defined glycopeptides and oligosaccharides as regulatory signals in their own right has led to a clearer appreciation of the physiologic role of these structures in regulating the cell cycle and state of cell activation as well as the view that these compounds represent a new class of agents with broad pharmaceutical activities. Dr. Mishra, working with Dr. Muchmore extended previous observations to implicate a common mechanism for the activity of these pluripotent glycopeptides. Their data demonstrate that high mannose glycopeptides in structurally specific fashion act directly in the nucleus to regulate gene transcription. Using the AP-1 model first described in HeLa cells, Dr. Muchmore showed that Man-5 phosphate blocks the ability of the heterodimeric transcription factors fos-jun to bind to their consensus DNA binding region. These observations have been expanded to show a functional effect not only on in vitro transcription but also on intact cellular proliferation. Specific mannose structures block the unbridled proliferation of HeLa cells and at least partially induce contact growth inhibition. This ability to apparently reverse the malignant phenotype of HeLa cells suggests that these studies offer an entirely new avenue of research in efforts to understand and control malignant cell growth. In addition studies with transfected fibroblast lines from patients show that disorder of CNS development in mannosidosis is probably caused by inhibition of AP-1-mediated gene transcription. In related studies Dr. Muchmore has defined a high affinity receptor specific for uromodulin, an inhibitor of lymphocyte proliferation. Furthermore, he has isolated and partially sequenced a cDNA clone from a human testis library which represents the human homologue of a sea urchin sperm protein known to have homology to uromodulin and to be functionally important in acrosomal body formation.
