David C. Seldin, MD, PhD

 
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PI: David C. Seldin, MD, PhD

Title: Professor of Medicine and Microbiology, Chief of the Section of Hematology-Oncology, Director, Amyloid Treatment & Research Program

Research interests: kinases, Wnt signaling, breast cancer, lymphoma, amyloidoisis

Clinical interests: amyloidosis, stem cell transplantation, hematologic malignancies

Research Overview:

My laboratory works in two areas: signal transduction and cancer, and AL amyloidosis. A unifying theme in the projects is the use of transgenic and knockout mouse models to understand disease pathophysiology.

CK2 in Cancer and Development 

MMTV-CK2 transgenic mammary tumor.

MMTV-CK2 transgenic mammary tumor.

In the area of oncogenic signaling, we focus on a serine-threonine kinase, protein kinase CK2 (formerly casein kinase II), that is a ubiquitous and highly conserved regulator of cell signaling; we have studied its role in lymphomagenesis and mammary tumorigenesis. It appears to be a regulator of NF-B activation (collaboration with the Sonenshein Lab) and of Wnt signaling (collaboration with the Dominguez Lab). It is upregulated in spontaneous and chemically-induced mammary tumorigenesis (collaboration with the Sherr Lab). We also study GSK3, another serine-threonine kinase that is a Wnt regulator. Overexpression of CK2 or a kinase inactive dominant negative GSK3 in transgenic mice produces mammary tumors with Wnt activation and progression to invasive “EMT-like” tumors.

Comparison of CK2+/+ (upper panels) and CK2-/- (lower panels) embryos (Lou et al.).

Comparison of CK2+/+ (upper panels) and CK2-/- (lower panels) embryos (Lou et al.).

In addition to characterizing pathological situations in which CK2 dysregulation leads to cancer, we are using gene targeting to characterize the essential development roles of the isoforms of CK. We have found that CK2’ is required for normal male germ cell development, and that CK2 is required for organogenesis in mid-gestation embryos.

AL Amyloidosis

Congo red amyloid deposits in the stomach of human 6 transgenic mice.

Congo red amyloid deposits in the stomach of human 6 transgenic mice.

The amyloidoses are diseases of protein misfolding, that include Alzheimer’s disease, for example. AL, or immunoglobulin light chain, amyloidosis is a clonal plasma cell disease in which the light chains polymerize and form fibrillar deposits in tissues leading to organ failure and death. We are examining the sequence and structure of amyloidogenic light chains, and developing animal models and therapeutics for the disease. Recently, we have engineered transgenic mice that develop AL amyloid deposits in the stomach. We also conduct clinical trials for treatment of AL amyloidosis, with stem cell transplantation and with novel agents. Other research in the Amyloid Treatment and Research Program is directed towards diagnostics and novel therapeutics for AF familial amyloidosis and age-related ATTR systemic amyloidosis.

Publications:

Selected recent papers  

Landesman-Bollag, E., R. Romieu-Mourez, D. H. Song, G. E. Sonenshein, R. D. Cardiff and D. C. Seldin Protein kinase CK2 in mammary gland tumorigenesis. Oncogene, 2001 20(25): 3247-57.

Song DH, Dominguez I, Mizuno J, Kaut M, Mohr SC, Seldin DC. CK2 phosphorylation of the armadillo repeat region of β-catenin potentiates Wnt signaling, J Biol Chem, 2003; 278:24018-25.

Dominguez I, Mizuno J, Wu H, Song D, Symes K, and Seldin DC. Protein kinase CK2 Is required for dorsal axis formation In Xenopus embryos, Developmental Biology, 2004; 274:110-24.

Farago M, Dominguez I, Landesman-Bollag E, Xu X, Patel S, Rosner A, Cardiff RD, Seldin DC. Kinase-inactive glycogen synthase kinase 3β promotes Wnt signaling and mammary tumorigenesis, Cancer Research, 2005; 65: 5792-5801.

Currier N,  Solomon SE, Demicco EG, Chang DLF , Farago M, Ying H, Dominguez I, Sonenshein GE, Cardiff RD, Xiao ZJ, Sherr DH, Seldin DC. Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors, Toxicol. Pathol., 2005; 33:726-737.

Sanchorawala V, Skinner M, Quillen K, Finn KT, Doros G, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation, Blood 110(10):3561-3.

Connors LH, Jiang Y, Budnik M, Théberge R, Prokaeva T, Bodi KL, Seldin DC, Costello CE, Skinner M. Heterogeneity in Primary Structure, Post-Translational Modifications, and Germline Gene Usage of Nine Full-Length Amyloidogenic kappa1 Immunoglobulin Light Chains. Biochemistry. 2007 Dec 11;46(49):14259-71.

Belguise K, Guo S, Yang S, Rogers AE, Seldin DC, Sherr DH, and Sonenshein GE. Green Tea Polyphenols Reverse Cooperation between c-Rel and CK2 that Induces the Aryl Hydrocarbon Receptor, Slug and an Invasive Phenotype, Cancer Research 2007 67(24):11742-5.

Lou DY, Dominguez I, Toselli P, Landesman-Bollag E, O’Brien C, and Seldin DC. The Alpha Catalytic Subunit of Protein Kinase CK2 Is Required For Mouse Embryonic Development, Mol Cell Biol. 2008, 28(1):131-9.

Lavatelli F, Perlman DH, Spencer B, Prokaeva T, McComb ME, Théberge R, Connors LH, Bellotti V, Seldin DC, Merlini G, Skinner M, Costello CE. Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue. Mol Cell Proteomics. 2008 Aug;7(8):1570-83.

Seldin DC, Lou DY, Toselli P, Landesman-Bollag E, Dominguez I. Gene targeting of CK2 catalytic subunits. Mol Cell Biochem. 316 (1-2):141-7.

Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI, Bharti A, Seldin DC, Lecker SH, Dominguez I, Cohen HT. Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol. 2008, 10 (10):1208-16.

Belguise K, Guo S, Yang S, Rogers AE, Seldin DC, Sherr DH, and Sonenshein GE. Green Tea Polyphenols Reverse Cooperation between c-Rel and CK2 that Induces the Aryl Hydrocarbon Receptor, Slug and an Invasive Phenotype, Cancer Research 2007 67(24):11742-5.

Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI, Bharti A, Seldin DC, Lecker SH, Dominguez I, Cohen HT.Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol. 2008 Oct;10(10):1208-16.

Girnius S, Seldin DC, Skinner M, Finn KT, Quillen K, Doros G, and Sanchorawala V. Short and long-term outcome of treatment with high-dose melphalan and stem cell transplantation for multiple myeloma-associated AL amyloidosis. Ann Hematol. 2010 Jun;89(6):579-84.

Currier N, Chea K, Hlavacova M, Sussman DJ, Seldin DC, Dominguez I. Dynamic expression of a LEF-EGFP Wnt reporter in mouse development and cancer. Genesis. 2010 Mar;48(3):183-94.

Landesman-Bollag E, Belkina A, Hovey B, Connors E, Cox C, Seldin DC. Developmental and growth defects in mice with combined deficiency of CK2 catalytic genes. Mol Cell Biochem. 2011 Oct; 356(1-2):227-31.

Ward JE, Ren R, Toraldo G, Soo Hoo P, Guan J, O’Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, and Seldin DC. Doxycycline Reduces Fibril Formation in a Transgenic Mouse Model of AL Amyloidosis. Blood. 2011 Dec 15; 118(25):6610-7.

Hovey BM, Ward JE, Soo Hoo P, O’Hara CJ, Connors LH, Seldin DC.  Preclinical development of siRNA therapeutics for AL amyloidosis.  Gene Ther. 2011 Dec; 18(12):1150-6. doi: 10.1038/gt.2011.69.

Sanchorawala V, Quillen K, Sloan JM, Andrea NT, Seldin DC. Bortezomib and high-dose melphalan conditioning for stem cell transplantation for AL amyloidosis: a pilot study.  Haematologica. 2011 Dec; 96(12):1890-2.

Imbrie G, Wu H, Seldin DC, Dominguez I. Asymmetric localization of CK2α during Xenopus oogenesis. Human Genetics & Embryology, in press.

Lab group en route to the CK2-IV meeting in London, Ontario.

Lab group en route to the CK2-IV meeting in London, Ontario.

 

The Seldin Lab:

Esther Landesman-Bollag, PhD

Jennifer Ellis-Ward, PhD

Varuna Shibad, MS

 

 

 

Primary teaching affiliate
of BU School of Medicine