William Philbrick, PhD
Senior Research Scientist in Medicine (Endocrinology); Director, Diabetes Endocrinology Research Center Molecular Core
Research & Publications
Biography
News
Research Summary
Parathyroid hormone-related peptide (PTHrP) is a multifunctional protein which plays a role in the inhibition of programmed differentiation in a number of systems. To explore the role of this peptide in development, we have taken a targeted overexpression approach using transgenic mice. In the epidermis, PTHrP delays hair follicle initiation, while in the mammary gland and bone, it acts as a potent inhibitor of branching morphogenesis and endochondral ossification, respectively. Current projects include further characterization of these systems both in vivo and in vitro and investigation of the role of PTHrP in the development of the lung and the immune system.
When overproduced by tumors, PTHrP can enter the circulation and react with classical PTH receptors in bone and kidney resulting in hypercalcemia. We have found that PTHrP gene expression is regulated by methylation of critical sites in the promoter, by the levels of specific trans-acting factors, and finally by stabilization of the tumor suppressor, p53. We are presently engaged in characterizing the nature of the DNA-protein interactions involved in all three mechanisms.
Specialized Terms: Parathyroid hormone-related peptide (PTHrP)
Coauthors
Research Interests
Diabetes Mellitus; Endocrinology; Parathyroid Hormone-Related Protein
Selected Publications
- Compromised Host Stem Cell Competitiveness Affords Fanconi Stem Cell Engraftment in C-Kit Mutant Humanized MiceLIU W, Song Y, Gbyli R, Sefik E, Biancon G, Gao Y, Philbrick W, Patel A, Tebaldi T, Nalepa G, Kupfer G, Flavell R, Halene S. Compromised Host Stem Cell Competitiveness Affords Fanconi Stem Cell Engraftment in C-Kit Mutant Humanized Mice Blood 2021, 138: 1119-1119. DOI: 10.1182/blood-2021-153777.
- NLRP6 Inflammasome Orchestrates the Colonic Host-Microbial Interface by Regulating Goblet Cell Mucus SecretionWlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang JP, Brown EM, Frankel G, Levy M, Katz MN, Philbrick WM, Elinav E, Finlay BB, Flavell RA. NLRP6 Inflammasome Orchestrates the Colonic Host-Microbial Interface by Regulating Goblet Cell Mucus Secretion Cell 2014, 156: 1045-1059. PMID: 24581500, PMCID: PMC4017640, DOI: 10.1016/j.cell.2014.01.026.
- Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle*Löffler MG, Birkenfeld AL, Philbrick KM, Belman JP, Habtemichael EN, Booth CJ, Castorena CM, Choi CS, Jornayvaz FR, Gassaway BM, Lee HY, Cartee GD, Philbrick W, Shulman GI, Samuel VT, Bogan JS. Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle* Journal Of Biological Chemistry 2013, 288: 20135-20150. PMID: 23744065, PMCID: PMC3711282, DOI: 10.1074/jbc.m113.458075.
- Parathyroid‐Hormone‐Related Protein is a Neuroprotective Endogenous Regulator of L‐Type Calcium ChannelsChatterjee O, Nakchbandi I, Philbrick W, Kaczmarek L, Brines M, Broadus A. Parathyroid‐Hormone‐Related Protein is a Neuroprotective Endogenous Regulator of L‐Type Calcium Channels CNS Neuroscience & Therapeutics 2006, 6: 42-42. DOI: 10.1111/j.1527-3458.2000.tb00185.x.
- Insulin secretion and IP levels in two distant lineages of the genus Mus: comparisons with rat isletsZawalich W, Zawalich K, Tesz G, Sterpka J, Philbrick W. Insulin secretion and IP levels in two distant lineages of the genus Mus: comparisons with rat islets AJP Endocrinology And Metabolism 2001, 280: e720-e728. PMID: 11287354, DOI: 10.1152/ajpendo.2001.280.5.e720.
- Absence of Functional Type 1 Parathyroid Hormone (PTH)/PTH-Related Protein Receptors in Humans Is Associated with Abnormal Breast Development and Tooth Impaction 1Wysolmerski J, Cormier S, Philbrick W, Dann P, Zhang J, Roume J, Delezoide A, Silve C. Absence of Functional Type 1 Parathyroid Hormone (PTH)/PTH-Related Protein Receptors in Humans Is Associated with Abnormal Breast Development and Tooth Impaction 1 The Journal Of Clinical Endocrinology & Metabolism 2001, 86: 1788-1794. DOI: 10.1210/jcem.86.4.7404.
- Chapter 3 Parathyroid Hormone-Related Protein Gene Structure, Biosynthesis, Metabolism, and RegulationPhilbrick W. Chapter 3 Parathyroid Hormone-Related Protein Gene Structure, Biosynthesis, Metabolism, and Regulation 2001, 31-51. DOI: 10.1016/b978-012098651-4/50005-5.
- βiv Spectrin, a New Spectrin Localized at Axon Initial Segments and Nodes of Ranvier in the Central and Peripheral Nervous SystemBerghs S, Aggujaro D, Dirkx R, Maksimova E, Stabach P, Hermel J, Zhang J, Philbrick W, Slepnev V, Ort T, Solimena M. βiv Spectrin, a New Spectrin Localized at Axon Initial Segments and Nodes of Ranvier in the Central and Peripheral Nervous System Journal Of Cell Biology 2000, 151: 985-1002. PMID: 11086001, PMCID: PMC2174349, DOI: 10.1083/jcb.151.5.985.
- Parathyroid hormone-related protein induces spontaneous osteoclast formation via a paracrine cascadeNakchbandi I, Weir E, Insogna K, Philbrick W, Broadus A. Parathyroid hormone-related protein induces spontaneous osteoclast formation via a paracrine cascade Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 7296-7300. PMID: 10829073, PMCID: PMC16539, DOI: 10.1073/pnas.110553397.
- Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia*Garcia-Ocaña A, Takane K, Syed M, Philbrick W, Vasavada R, Stewart A. Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia* Journal Of Biological Chemistry 2000, 275: 1226-1232. PMID: 10625667, DOI: 10.1074/jbc.275.2.1226.
- Regulation of parathyroid hormone-related protein gene expression in murine keratinocytes by E1A isoforms: a role for basal promoter and Ets-1 siteFoley J, Wysolmerski J, Missero C, King C, Philbrick W. Regulation of parathyroid hormone-related protein gene expression in murine keratinocytes by E1A isoforms: a role for basal promoter and Ets-1 site Molecular And Cellular Endocrinology 1999, 156: 13-23. PMID: 10612419, DOI: 10.1016/s0303-7207(99)00151-3.
- PTHrP Regulates Epidermal Differentiation in Adult MiceFoley J, Wysolmerski J, Dreyer B, Broadus A, Philbrick W, Longely B. PTHrP Regulates Epidermal Differentiation in Adult Mice Journal Of Investigative Dermatology 1998, 111: 1122-1128. PMID: 9856827, DOI: 10.1046/j.1523-1747.1998.00428.x.
- Parathyroid hormone-related protein is required for tooth eruptionPhilbrick W, Dreyer B, Nakchbandi I, Karaplis A. Parathyroid hormone-related protein is required for tooth eruption Proceedings Of The National Academy Of Sciences Of The United States Of America 1998, 95: 11846-11851. PMID: 9751753, PMCID: PMC21728, DOI: 10.1073/pnas.95.20.11846.
- Parathyroid hormone‐related protein is a developmental regulatory moleculePhilbrick W. Parathyroid hormone‐related protein is a developmental regulatory molecule European Journal Of Oral Sciences 1998, 106: 32-37. PMID: 9541200, DOI: 10.1111/j.1600-0722.1998.tb02150.x.
- Bcl-2 Lies Downstream of Parathyroid Hormone–related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal DevelopmentAmling M, Neff L, Tanaka S, Inoue D, Kuida K, Weir E, Philbrick W, Broadus A, Baron R. Bcl-2 Lies Downstream of Parathyroid Hormone–related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal Development Journal Of Cell Biology 1997, 136: 205-213. PMID: 9008714, PMCID: PMC2132464, DOI: 10.1083/jcb.136.1.205.
- Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation.Weir E, Philbrick W, Amling M, Neff L, Baron R, Broadus A. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proceedings Of The National Academy Of Sciences Of The United States Of America 1996, 93: 10240-10245. PMID: 8816783, PMCID: PMC38368, DOI: 10.1073/pnas.93.19.10240.
- Overexpression of Parathyroid Hormone-related Protein in the Pancreatic Islets of Transgenic Mice Causes Islet Hyperplasia, Hyperinsulinemia, and Hypoglycemia (∗)Vasavada R, Cavaliere C, D'Ercole A, Dann P, Burtis W, Madlener A, Zawalich K, Zawalich W, Philbrick W, Stewart A. Overexpression of Parathyroid Hormone-related Protein in the Pancreatic Islets of Transgenic Mice Causes Islet Hyperplasia, Hyperinsulinemia, and Hypoglycemia (∗) Journal Of Biological Chemistry 1996, 271: 1200-1208. PMID: 8557651, DOI: 10.1074/jbc.271.2.1200.
- Further evidence for a novel receptor for amino-terminal parathyroid hormone-related protein on keratinocytes and squamous carcinoma cell lines.Orloff J, Kats Y, Urena P, Schipani E, Vasavada R, Philbrick W, Behal A, Abou-Samra A, Segre G, Jüppner H. Further evidence for a novel receptor for amino-terminal parathyroid hormone-related protein on keratinocytes and squamous carcinoma cell lines. Endocrinology 1995, 136: 3016-23. PMID: 7789327, DOI: 10.1210/endo.136.7.7789327.
- Cell Type-specific Secretion of Parathyroid Hormone-related Protein via the Regulated versus the Constitutive Secretory Pathway∗Plawner L, Philbrick W, Burtis W, Broadus A, Stewart A. Cell Type-specific Secretion of Parathyroid Hormone-related Protein via the Regulated versus the Constitutive Secretory Pathway∗ Journal Of Biological Chemistry 1995, 270: 14078-14084. PMID: 7775469, DOI: 10.1074/jbc.270.23.14078.
- The CD59 antigen is a structural homologue of murine Ly‐6 antigens but lacks interferon inducibilityPhilbrick W, Palfree R, Maher S, Bridgett M, Sirlin S, Bothwell A. The CD59 antigen is a structural homologue of murine Ly‐6 antigens but lacks interferon inducibility European Journal Of Immunology 1990, 20: 87-92. PMID: 1689664, DOI: 10.1002/eji.1830200113.
- Functional and Molecular Changes in Colony Stimulating Factor Secretion by OsteoblastsHorowitz M, Einhorn T, Philbrick W, Yale R. Functional and Molecular Changes in Colony Stimulating Factor Secretion by Osteoblasts Connective Tissue Research 1989, 20: 159-168. PMID: 2558840, DOI: 10.3109/03008208909023884.