The National Institute of Diabetes & Digestive & Kidney Diseases

There are two principal areas of research in my laboratory. The first aims to understand the pathogenesis and clinical spectrum of familial isolated hyperparathyroidism (FIHP), 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% of all affected by HPT-JT have parathyroid cancer, and nearly 10% 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 main focus of research in my laboratory effort 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 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 [R7BP], 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.

Zhang JH, Seigneur EM, Pandey M, Loshakov A, Dagur PK, Connelly PS, Koo L, Panicker LM, Simonds WF The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome. Cell Death Dis (Feb 2): 2012. [Full Text/Abstract]

Simonds WF, Varghese S, Marx SJ, Nieman LK Cushing's syndrome in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) (March): 2012. [Full Text/Abstract]

Zhang JH, Pandey M, Seigneur EM, Panicker LM, Koo L, Schwartz OM, Chen W, Chen CK, Simonds WF Knockout of G protein β5 impairs brain development and causes multiple neurologic abnormalities in mice. J Neurochem (Nov): 2012. [Full Text/Abstract]

Sharretts JM, Kebebew E, Simonds WF Parathyroid cancer. . Semin Oncol (Dec): 2010. [Full Text/Abstract]

Sharretts JM, Simonds WF Clinical and molecular genetics of parathyroid neoplasms. Best Pract Res Clin Endocrinol Metab (June): 2010. [Full Text/Abstract]

Zhang JH, Panicker LM, Seigneur EM, Lin L, House CD, Morgan W, Chen WC, Mehta H, Haj-Ali M, Yu ZX, Simonds WF Cytoplasmic polyadenylation element binding protein is a conserved target of tumor suppressor HRPT2/CDC73. Cell Death Differ (Mar 26): 2010. [Full Text/Abstract]

Panicker LM, Zhang JH, Dagur PK, Gastinger MJ, Simonds WF Defective nucleolar localization and dominant interfering properties of a parafibromin L95P missense mutant causing the hyperparathyroidism-jaw tumor syndrome. Endocr Relat Cancer (March 24): 2010. [Full Text/Abstract]

Panicker LM, Zhang JH, Posokhova E, Gastinger MJ, Martemyanov KA, Simonds WF Nuclear localization of the G protein beta5/R7-regulator of G protein signaling protein complex is dependent on R7 binding protein. J Neurochem (Jan 22): 2010. [Full Text/Abstract]

Lin L, Zhang JH, Panicker LM, Simonds WF The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene. Proc Natl Acad Sci U S A (45):17420-25, 2008. [Full Text/Abstract]

Marx SJ, Simonds WF Hereditary hormone excess: genes, molecular pathways, and syndromes. Endocr Rev (26): 615-61, 2005. [Full Text/Abstract]

Simonds WF, Woodard GE, Zhang JH Assays of nuclear localization of R7/Gbeta5 complexes. Methods Enzymol (390): 210-23, 2004. [Full Text/Abstract]

Simonds WF Robbins CM Agarwal SK Hendy GN Carpten JD Marx SJ Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab (89): 96-102, 2004. [Full Text/Abstract]

Simonds WF G protein-regulated signaling dysfunction in human disease. J Investig Med (51): 194-214, 2003. [Full Text/Abstract]

Rojkova AM Woodard GE Huang TC Combs CA Zhang JH Simonds WF Ggamma subunit-selective G protein beta 5 mutant defines regulators of G protein signaling protein binding requirement for nuclear localization. J Biol Chem (278): 12507-12, 2003. [Full Text/Abstract]

Weinstein LS Simonds WF HRPT2, a marker of parathyroid cancer. N Engl J Med (349): 1691-2, 2003. [Full Text/Abstract]

Simonds WF James-Newton LA Agarwal SK Yang B Skarulis MC Hendy GN Marx SJ Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) (81): 1-26, 2002. [Full Text/Abstract]

Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Hoog A, Heath H 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, et al HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genetics(32): 676-80, 2002. [Full Text/Abstract]

Zhang JH Barr VA Mo Y Rojkova AM Liu S Simonds WF Nuclear localization of G protein beta 5 and regulator of G protein signaling 7 in neurons and brain. J Biol Chem (276): 10284-9, 2001. [Full Text/Abstract]

Skiba NP Martemyanov KA Elfenbein A Hopp JA Bohm A Simonds WF Arshavsky VY RGS9-G beta 5 substrate selectivity in photoreceptors. Opposing effects of constituent domains yield high affinity of RGS interaction with the G protein-effector complex. J Biol Chem (276): 37365-72, 2001. [Full Text/Abstract]

Zhang JH Simonds WF Copurification of brain G-protein beta5 with RGS6 and RGS7. J Neurosci (20): RC59, 2000. [Full Text/Abstract]