Diabetes Mellitus; Endocrinology; Parathyroid Hormone-Related Protein
Skin Diseases Research Center, Yale
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)
Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle.
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. J Biol Chem. 2013 Jul 12;288(28):20135-50. doi: 10.1074/jbc.M113.458075. Epub 2013 Jun 6.
NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion.
NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Wlodarska 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. Cell. 2014 Feb 27;156(5):1045-59. doi: 10.1016/j.cell.2014.01.026.
Full List of PubMed Publications
- Yao C, Yu KP, Philbrick W, Sun BH, Simpson C, Zhang C, Insogna K: Breast cancer-associated gene 3 interacts with Rac1 and augments NF-κB signaling in vitro, but has no effect on RANKL-induced bone resorption in vivo. Int J Mol Med. 2017 Oct; 2017 Aug 4. PMID: 28791343
- Lester SG, Russo L, Ghanem SS, Khuder SS, DeAngelis AM, Esakov EL, Bowman TA, Heinrich G, Al-Share QY, McInerney MF, Philbrick WM, Najjar SM: Hepatic CEACAM1 Over-Expression Protects Against Diet-Induced Fibrosis and Inflammation in White Adipose Tissue. Front Endocrinol (Lausanne). 2015; 2015 Aug 3. PMID: 26284027
- Al-Share QY, DeAngelis AM, Lester SG, Bowman TA, Ramakrishnan SK, Abdallah SL, Russo L, Patel PR, Kaw MK, Raphael CK, Kim AJ, Heinrich G, Lee AD, Kim JK, Kulkarni RN, Philbrick WM, Najjar SM: Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance. Diabetes. 2015 Aug; 2015 May 13. PMID: 25972571
- Shroff EH, Eberlin LS, Dang VM, Gouw AM, Gabay M, Adam SJ, Bellovin DI, Tran PT, Philbrick WM, Garcia-Ocana A, Casey SC, Li Y, Dang CV, Zare RN, Felsher DW: MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci U S A. 2015 May 26; 2015 May 11. PMID: 25964345
- Wlodarska 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 Feb 27. PMID: 24581500
- 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. J Biol Chem. 2013 Jul 12; 2013 Jun 6. PMID: 23744065
- Strowig T, Rongvaux A, Rathinam C, Takizawa H, Borsotti C, Philbrick W, Eynon EE, Manz MG, Flavell RA: Transgenic expression of human signal regulatory protein alpha in Rag2-/-gamma(c)-/- mice improves engraftment of human hematopoietic cells in humanized mice. Proc Natl Acad Sci U S A. 2011 Aug 9; 2011 Jul 25. PMID: 21788509
- Wu M, Hesse E, Morvan F, Zhang JP, Correa D, Rowe GC, Kiviranta R, Neff L, Philbrick WM, Horne WC, Baron R: Zfp521 antagonizes Runx2, delays osteoblast differentiation in vitro, and promotes bone formation in vivo. Bone. 2009 Apr; 2008 Nov 27. PMID: 19095088
- Morino K, Neschen S, Bilz S, Sono S, Tsirigotis D, Reznick RM, Moore I, Nagai Y, Samuel V, Sebastian D, White M, Philbrick W, Shulman GI: Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle. Diabetes. 2008 Oct; 2008 Jul 15. PMID: 18633112
- Sabatakos G, Rowe GC, Kveiborg M, Wu M, Neff L, Chiusaroli R, Philbrick WM, Baron R: Doubly truncated FosB isoform (Delta2DeltaFosB) induces osteosclerosis in transgenic mice and modulates expression and phosphorylation of Smads in osteoblasts independent of intrinsic AP-1 activity. J Bone Miner Res. 2008 May. PMID: 18433296
- Yamazaki H, Philbrick W, Zawalich KC, Zawalich WS: Acute and chronic effects of glucose and carbachol on insulin secretion and phospholipase C activation: studies with diazoxide and atropine. Am J Physiol Endocrinol Metab. 2006 Jan; 2005 Aug 16. PMID: 16105864
- Chen X, Macica CM, Dreyer BE, Hammond VE, Hens JR, Philbrick WM, Broadus AE: Initial characterization of PTH-related protein gene-driven lacZ expression in the mouse. J Bone Miner Res. 2006 Jan; 2005 Oct 10. PMID: 16355280
- Zawalich WS, Tesz GJ, Yamazaki H, Zawalich KC, Philbrick W: Dexamethasone suppresses phospholipase C activation and insulin secretion from isolated rat islets. Metabolism. 2006 Jan. PMID: 16324917
- Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R: Fibroblast growth factor 7: an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab. 2005 Feb; 2004 Nov 23. PMID: 15562028
- Kveiborg M, Sabatakos G, Chiusaroli R, Wu M, Philbrick WM, Horne WC, Baron R: DeltaFosB induces osteosclerosis and decreases adipogenesis by two independent cell-autonomous mechanisms. Mol Cell Biol. 2004 Apr. PMID: 15024071
- Zawalich WS, Zawalich KC, Tesz GJ, Taketo MM, Sterpka J, Philbrick W, Matsui M: Effects of muscarinic receptor type 3 knockout on mouse islet secretory responses. Biochem Biophys Res Commun. 2004 Mar 19. PMID: 14985093
- Chatterjee O, Nakchbandi IA, Philbrick WM, Dreyer BE, Zhang JP, Kaczmarek LK, Brines ML, Broadus AE: Endogenous parathyroid hormone-related protein functions as a neuroprotective agent. Brain Res. 2002 Mar 15. PMID: 11879796