The purpose of my research is to try to understand the causes of parathyroid tumors, including malignant parathyroid tumors, and to understand the regulation of G protein signaling in brain and hormonal tissue.
There are two principal areas of research in my laboratory. The first aims to understand the pathogenesis and clinical spectrum of familial isolated hyperparathyroidism, parathyroid cancer, and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). HPT-JT is a familial syndrome of HPT with autosomal dominant transmission and high but incomplete and variable penetrance. Some 15 percent of all affected by HPT-JT have parathyroid cancer, and nearly 10 percent of adult cases appear to be silent carriers. The trait links to the CDC73/HRPT2 locus at 1q25-q31. CDC73/HRPT2 is a widely expressed, evolutionarily conserved gene encoding parafibromin, a predominantly nuclear protein of 531 amino acids. Parafibromin is a component of the evolutionarily conserved PAF1 transcriptional regulatory complex. CDC73/HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and parathyroid cancer. Current studies employ mammalian and Drosophila model systems to explore the key molecular mechanisms by which loss of parafibromin function promotes neoplasia.
The other focus of research in my laboratory concentrates on the G protein β5 complex with regulator of G protein signaling (RGS) proteins. G protein β5 is a neuronally expressed, structurally divergent G protein β isoform, which may be functionally specialized. In general, RGS proteins act as GTPase activating proteins targeting Gα subunits and thus can help turn off G protein signalling; recent evidence suggests, however, that certain RGS proteins can also function as signal transducers or effectors in their own right. The observations that G β5 forms a tight complex with RGS proteins of the R7 subclass in the brain, and that such complexes are expressed in the cell nucleus and cytoplasm (in addition to the plasma membrane where the complex is anchored by binding to R7 binding protein, an acylated SNARE-like protein), are unexplained by current models of G protein signalling. We are seeking to better understand the function of the highly conserved Gβ5/ R7 RGS protein heterodimers in brain and neuroendocrine cells.
Applying our Research
This research may help in the diagnosis and therapy of benign and malignant parathyroid tumors, and perhaps other types of tumors. Better understanding of G protein-regulated signaling in brain and hormonal tissue may allow the identification of targets for therapeutic agents to selectively enhance or inhibit neuronal or hormonal signaling.
Need for Further Study
Further research is required to explore other tumors or malignancies that might be related to inactivation of the CDC73/HRPT2 gene.