Mark P. de Caestecker, M.D., Ph.D.
Assistant Professor of Medicine (Nephrology)
Vanderbilt University Medical Center
S-3223 Medical Center North
Nashville, TN 37232
Kidney regeneration and therapy, kidney development, pulmonary vasculature, genetics, BMP signaling, IPS cells
There are three main areas of research in my lab:
1) Our laboratory is interested in the mechanisms regulating kidney development and how these processes are abnormally regulated in kidney injury and malignancy (Wilms tumor). Studes from my lab have mainly focused on the role of Cited1, 2 and 4, a family of transcriptional co-activators that are involved in regulating fate and migration of epithelial progenitor cells in during renal development. In addition, based on our evaluation of Cited1 knockout mice, we are investigating the fetal programming defects resulting from intrauterine growth retardation that promote abnormal embryonic kidney development and chronic kidney disease in adults.
2) We are currently extending our developmental studies to explore how some of these developmental regulated pathways are reactivated in regerenating tissues following acute kidney injury and studying their role in promoting normal tissue regeneration. Based on these studies we are testing novel thereapeutic approaches, identified from high content screens in zebrafish embryos (in collaboration with Neil Hukreide from the University of Pittsburgh) , that enhance these regnerative developmental programs, increase the rate of recovery and reduce long term scarring following acute kidney injury in mice.
3) The other focus in my lab is on the functional role of BMP signaling in pulmonary hypertension. Human genetic studies indicate that this signaling pathway plays an important role in modifying pulmonary vascular responses in disease. Studies from my lab have shown that Bmp signaling exerts distinct opposing, cell specific effects on pulmonary vascular remodeling and tone. We are currently using genetic models in mice and patient derived IPS cells to evaluate effect of inherited mutations in the BMP type 2 receptor, BMPR2, on pulmonary vascular cell function, and using these approaches to evaluate the use of mutation-specific therapies to improve pulmonary vascular function in patients with heritable forms of pulmonary hypertension
- Murphy, AJ, Axt, JR, de Caestecker, C, Pierce, J, Correa, H, Seeley, EH, Caprioli, RM, Newton, MW, de Caestecker, MP, Lovvorn, HN Molecular characterization of Wilms'' tumor from a resource-constrained region of sub-Saharan Africa. Int J Cancer, 131(6), E983-94, 2012.
- Murphy, AJ, Pierce, J, de Caestecker, C, Taylor, C, Anderson, JR, Perantoni, AO, de Caestecker, MP, Lovvorn, HN SIX2 and CITED1, markers of nephronic progenitor self-renewal, remain active in primitive elements of Wilms'' tumor. J Pediatr Surg, 47(6), 1239-49, 2012.
- Novitskaya, T, Baserga, M, de Caestecker, MP Organ-specific defects in insulin-like growth factor and insulin receptor signaling in late gestational asymmetric intrauterine growth restriction in Cited1 mutant mice. Endocrinology, 152(6), 2503-16, 2011.
- Zhang, MZ, Su, Y, Yao, B, Zheng, W, Decaestecker, M, Harris, RC Assessing the Application of Tissue Microarray Technology to Kidney Research. J Histochem Cytochem, 2010.
- Lowery, JW, de Caestecker, MP BMP signaling in vascular development and disease. Cytokine Growth Factor Rev, 21(4), 287-98, 2010.
- Anderson, L, Lowery, JW, Frank, DB, Novitskaya, T, Jones, M, Mortlock, DP, Chandler, RL, de Caestecker, MP Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol, 298(3), R833-42, 2010.
- Lowery, JW, Frump, AL, Anderson, L, DiCarlo, GE, Jones, MT, de Caestecker, MP ID family protein expression and regulation in hypoxic pulmonary hypertension. Am J Physiol Regul Integr Comp Physiol, 299(6), R1463-77, 2010.
- Langworthy, M, Zhou, B, de Caestecker, M, Moeckel, G, Baldwin, HS NFATc1 identifies a population of proximal tubule cell progenitors. J Am Soc Nephrol, 20(2), 311-21, 2009.
- Sparrow, DB, Boyle, SC, Sams, RS, Mazuruk, B, Zhang, L, Moeckel, GW, Dunwoodie, SL, de Caestecker, MP Placental insufficiency associated with loss of Cited1 causes renal medullary dysplasia. J Am Soc Nephrol, 20(4), 777-86, 2009.
- Boyle, S, Misfeldt, A, Chandler, KJ, Deal, KK, Southard-Smith, EM, Mortlock, DP, Baldwin, HS, de Caestecker, M Fate mapping using Cited1-CreERT2 mice demonstrates that the cap mesenchyme contains self-renewing progenitor cells and gives rise exclusively to nephronic epithelia. Dev Biol, 313(1), 234-45, 2008.
- Frank, DB, Lowery, J, Anderson, L, Brink, M, Reese, J, de Caestecker, M Increased susceptibility to hypoxic pulmonary hypertension in Bmpr2 mutant mice is associated with endothelial dysfunction in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol, 294(1), L98-109, 2008.
- de Caestecker, MP Angiopoietin-2 and glomerular proteinuria. J Am Soc Nephrol, 18(8), 2217-8, 2007.
- Lovvorn, HN, Westrup, J, Opperman, S, Boyle, S, Shi, G, Anderson, J, Perlman, EJ, Perantoni, AO, Wills, M, de Caestecker, M CITED1 expression in Wilms'' tumor and embryonic kidney. Neoplasia, 9(7), 589-600, 2007.
- Boyle, S, Shioda, T, Perantoni, AO, de Caestecker, M Cited1 and Cited2 are differentially expressed in the developing kidney but are not required for nephrogenesis. Dev Dyn, 236(8), 2321-30, 2007.
- Lovvorn, HN, Boyle, S, Shi, G, Shyr, Y, Wills, ML, Perantoni, AO, de Caestecker, M Wilms'' tumorigenesis is altered by misexpression of the transcriptional co-activator, CITED1. J Pediatr Surg, 42(3), 474-81, 2007.
- Chen, J, Boyle, S, Zhao, M, Su, W, Takahashi, K, Davis, L, Decaestecker, M, Takahashi, T, Breyer, MD, Hao, CM Differential expression of the intermediate filament protein nestin during renal development and its localization in adult podocytes. J Am Soc Nephrol, 17(5), 1283-91, 2006.
- Wang, S, de Caestecker, M, Kopp, J, Mitu, G, Lapage, J, Hirschberg, R Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol, 17(9), 2504-12, 2006.
- Boyle, S, de Caestecker, M Role of transcriptional networks in coordinating early events during kidney development. Am J Physiol Renal Physiol, 291(1), F1-8, 2006.
- de Caestecker, M Serotonin signaling in pulmonary hypertension. Circ Res, 98(10), 1229-31, 2006.
- Shi, G, Boyle, SC, Sparrow, DB, Dunwoodie, SL, Shioda, T, de Caestecker, MP The transcriptional activity of CITED1 is regulated by phosphorylation in a cell cycle-dependent manner. J Biol Chem, 281(37), 27426-35, 2006.
- Frank, DB, Abtahi, A, Yamaguchi, DJ, Manning, S, Shyr, Y, Pozzi, A, Baldwin, HS, Johnson, JE, de Caestecker, MP Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ Res, 97(5), 496-504, 2005.
- Frank, D, Johnson, J, de Caestecker, M Bone morphogenetic protein 4 promotes vascular remodeling in hypoxic pulmonary hypertension. Chest, 128(6 Suppl), 590S-591S, 2005.
- Plisov, S, Tsang, M, Shi, G, Boyle, S, Yoshino, K, Dunwoodie, SL, Dawid, IB, Shioda, T, Perantoni, AO, de Caestecker, MP Cited1 is a bifunctional transcriptional cofactor that regulates early nephronic patterning. J Am Soc Nephrol, 16(6), 1632-44, 2005.
- Chacko, Benoy M, Qin, Bin Y, Tiwari, Ashutosh, Shi, Genbin, Lam, Suvana, Hayward, Lawrence J, De Caestecker, Mark, Lin, Kai Structural basis of heteromeric smad protein assembly in TGF-beta signaling. Mol Cell, 15(5), 813-23, 2004.
- de Caestecker, Mark The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev, 15(1), 1-11, 2004.
- Hayashida, Tomoko, Decaestecker, Mark, Schnaper, H William Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-beta-dependent responses in human mesangial cells. FASEB J, 17(11), 1576-8, 2003.
- de Caestecker, Mark P, Bottomley, Martyn, Bhattacharyya, Sucharita, Payne, Tracie L, Roberts, Anita B, Yelick, Pamela C The novel type I serine-threonine kinase receptor Alk8 binds TGF-beta in the presence of TGF-betaRII. Biochem Biophys Res Commun, 293(5), 1556-65, 2002.
- De Caestecker, M, Meyrick, B Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension. Respir Res, 2(4), 193-7, 2001.
- Parks, W T, Frank, D B, Huff, C, Renfrew Haft, C, Martin, J, Meng, X, de Caestecker, M P, McNally, J G, Reddi, A, Taylor, S I, Roberts, A B, Wang, T, Lechleider, R J Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases. J Biol Chem, 276(22), 19332-9, 2001.
- Qin, B Y, Chacko, B M, Lam, S S, de Caestecker, M P, Correia, J J, Lin, K Structural basis of Smad1 activation by receptor kinase phosphorylation. Mol Cell, 8(6), 1303-12, 2001.
- Chacko, B M, Qin, B, Correia, J J, Lam, S S, de Caestecker, M P, Lin, K The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization. Nat Struct Biol, 8(3), 248-53, 2001.
- Lee, D K, Park, S H, Yi, Y, Choi, S G, Lee, C, Parks, W T, Cho, H, de Caestecker, M P, Shaul, Y, Roberts, A B, Kim, S J The hepatitis B virus encoded oncoprotein pX amplifies TGF-beta family signaling through direct interaction with Smad4: potential mechanism of hepatitis B virus-induced liver fibrosis. Genes Dev, 15(4), 455-66, 2001.
- Watanabe, H, de Caestecker, M P, Yamada, Y Transcriptional cross-talk between Smad, ERK1/2, and p38 mitogen-activated protein kinase pathways regulates transforming growth factor-beta-induced aggrecan gene expression in chondrogenic ATDC5 cells. J Biol Chem, 276(17), 14466-73, 2001.
- Larisch, S, Yi, Y, Lotan, R, Kerner, H, Eimerl, S, Tony Parks, W, Gottfried, Y, Birkey Reffey, S, de Caestecker, M P, Danielpour, D, Book-Melamed, N, Timberg, R, Duckett, C S, Lechleider, R J, Steller, H, Orly, J, Kim, S J, Roberts, A B A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif. Nat Cell Biol, 2(12), 915-21, 2000.
- Kim, R H, Wang, D, Tsang, M, Martin, J, Huff, C, de Caestecker, M P, Parks, W T, Meng, X, Lechleider, R J, Wang, T, Roberts, A B A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev, 14(13), 1605-16, 2000.
- de Caestecker, M P, Piek, E, Roberts, A B Role of transforming growth factor-beta signaling in cancer. J Natl Cancer Inst, 92(17), 1388-402, 2000.
- Yahata, T, de Caestecker, M P, Lechleider, R J, Andriole, S, Roberts, A B, Isselbacher, K J, Shioda, T The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors. J Biol Chem, 275(12), 8825-34, 2000.
- de Caestecker, M P, Yahata, T, Wang, D, Parks, W T, Huang, S, Hill, C S, Shioda, T, Roberts, A B, Lechleider, R J The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain. J Biol Chem, 275(3), 2115-22, 2000.
- Tsang, M, Kim, R, de Caestecker, M P, Kudoh, T, Roberts, A B, Dawid, I B Zebrafish nma is involved in TGFbeta family signaling. Genesis, 28(2), 47-57, 2000.
- Poncelet, A C, de Caestecker, M P, Schnaper, H W The transforming growth factor-beta/SMAD signaling pathway is present and functional in human mesangial cells. Kidney Int, 56(4), 1354-65, 1999.
- Vindevoghel, L, Lechleider, R J, Kon, A, de Caestecker, M P, Uitto, J, Roberts, A B, Mauviel, A SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor beta. Proc Natl Acad Sci U S A, 95(25), 14769-74, 1998.
- de Caestecker, M P, Parks, W T, Frank, C J, Castagnino, P, Bottaro, D P, Roberts, A B, Lechleider, R J Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases. Genes Dev, 12(11), 1587-92, 1998.
- Shioda, T, Lechleider, R J, Dunwoodie, S L, Li, H, Yahata, T, de Caestecker, M P, Fenner, M H, Roberts, A B, Isselbacher, K J Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator. Proc Natl Acad Sci U S A, 95(17), 9785-90, 1998.
- de Caestecker, M P, Hemmati, P, Larisch-Bloch, S, Ajmera, R, Roberts, A B, Lechleider, R J Characterization of functional domains within Smad4/DPC4. J Biol Chem, 272(21), 13690-6, 1997.
- Lechleider, R J, de Caestecker, M P, Dehejia, A, Polymeropoulos, M H, Roberts, A B Serine phosphorylation, chromosomal localization, and transforming growth factor-beta signal transduction by human bsp-1. J Biol Chem, 271(30), 17617-20, 1996.
- Mallick, N P, de Caestecker, M P The changing population on renal replacement therapy: its clinical and economic impact in Europe. Nephrol Dial Transplant, 11 Suppl 22-5, 1996.
- de Caestecker, M P, Bottomley, M, Telfer, B A, Hutchinson, I V, Vose, B M, Ballardie, F W Detection of abnormal peripheral blood mononuclear cell cytokine networks in human IgA nephropathy. Kidney Int, 44(6), 1298-308, 1993.
- de Caestecker, M P, Telfer, B A, Hutchinson, I V, Ballardie, F W The detection of intracytoplasmic interleukin-1 alpha, interleukin-1 beta and tumour necrosis factor alpha expression in human monocytes using two colour immunofluorescence flow cytometry. J Immunol Methods, 154(1), 11-20, 1992.
- de Caestecker, M P, Ballardie, F W Volumetric analysis of urinary erythrocytes: a standardized methodology to localize the source of haematuria. Am J Nephrol, 12(1-2), 41-8, 1992.
- de Caestecker, M P, Hall, C L, MacIver, A G Atypical antiglomerular basement membrane disease associated with thin membrane nephropathy. Nephrol Dial Transplant, 5(11), 909-13, 1990.
- de Caestecker, M P, Ballardie, F W Unexplained haematuria. BMJ, 301(6762), 1171-2, 1990.
- de Caestecker, M P, Hall, C L, Basterfield, P T, Smith, J G Localisation of haematuria by red cell analysers and phase contrast microscopy. Nephron, 52(2), 170-3, 1989.