Finkielstein Research Group

Capelluto Research Group (2018)

Our laboratory currently studies the molecular mechanisms of the circadian clock and the cell cycle, with emphasis on how they interface with one another. We explore how these interfaces contribute to the growth of cancer and how an in-depth understanding of them can be used to help develop anti-cancer therapies.

A fundamental feature of all living organisms is the presence of two 24-hour oscillating cyclic systems, the circadian clock and the cell cycle. The circadian clock dictates the timing of many physiological responses and provides the cell with information that can be used to anticipate daily environmental changes. The cell cycle is a series of synchronized events involving the growth, replication, and division of cells. The proper timing of cell division is a major factor contributing to the regulation of normal growth and emerges as a fundamental process in the development of most cancers. Our laboratory investigates some of the basic mechanisms that regulate cell cycle transitions, the contribution of environmental cues to ensure timely progression throughout it, and how both cycles are interlocked at the molecular level.

Adaptor Proteins in Endosomal Protein Trafficking

Ubiquitylation is a highly controlled post-translational modification of proteins, in which proteins are conjugated either with monoubiquitin or polyubiquitin chains. Ubiquitin modifications on target proteins are recognized by ubiquitin-binding domains, which are found in several effector proteins. We study the function and structure of the Toll-interacting protein (Tollip), which contains the C2 and CUE ubiquitin-binding domains and participates in the innate immune signaling pathway and endosomal protein trafficking.

Lipid-binding Events in the Wnt Signaling Pathway

The Wnt-dependent, b-catenin-independent pathway modulates cell movement and behavior. A downstream regulator of this signaling pathway is Dishevelled (Dvl), which among other multiple interactions, binds to the Frizzled receptor and the plasma membrane via phosphatidic acid (PA) in a mechanism proposed to be pH dependent. We defined the structural and functional basis of PA recognition by the Dvl2 DEP domain. We also established that PA binding by the Dvl2 DEP domain is pH-dependent and resembles the mechanism of PA deprotonation.

Modulators of Platelet Aggregation

Platelets form a clump at the site of vascular injury to stop bleeding. One negative regulator of platelet aggregation is Disabled-2 (Dab2), a protein released to the extracellular surface upon platelet activation. Dab2 inhibits platelet aggregation by competing with fibrinogen for alphaIIb-beta3 integrin receptor binding. The inhibitory role of Dab2 depends on its recognition to sulfatides, sphingolipids found on the platelet surface, which interact with coagulation proteins, playing a major role in haemostasis.

Lab Members

Name
Title

Bock, Abigail

Visiting Student

Henley, Kavon

Visiting Student

Lawrence, Brittany

Visiting Student

Oker, Helen

Visiting Student

Soccio-Mallon, Alexandra

Visiting Student

Wisdom, Esther

Visiting Student

Zou, Xianlin

Visiting Student

2015

Gotoh T, Vila-Caballer M, Liu J, Schiffhauer S, Finkielstein CV. Association of the circadian factor Period 2 to p53 influences p53's function in DNA-damage signaling. Mol Biol Cell. 2015;26:359–372.  http://www.ncbi.nlm.nih.gov/pubmed/25411341

Xiao S, Brannon MK, Zhao X, et al. Tom1 Modulates Binding of Tollip to Phosphatidylinositol 3-Phosphate via a Coupled Folding and Binding Mechanism. Structure. 2015;23:1910–1920.  http://www.ncbi.nlm.nih.gov/pubmed/26320582

2014

Capelluto DG, Zhao X, Lucas A, et al. Biophysical and molecular-dynamics studies of phosphatidic acid binding by the Dvl-2 DEP domain. Biophys J. 2014;106:1101–1111.  http://www.ncbi.nlm.nih.gov/pubmed/24606934

Gotoh T, Vila-Caballer M, Santos CS, Liu J, Yang J, Finkielstein CV. The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells. Mol Biol Cell. 2014;25:3081–3093.  http://www.ncbi.nlm.nih.gov/pubmed/25103245

Lucas AT, Fu X, Liu J, et al. Ligand binding reveals a role for heme in translationally-controlled tumor protein dimerization. PLoS One. 2014;9:e112823.  http://www.ncbi.nlm.nih.gov/pubmed/25396429

Xiao S, Zhao X, Finkielstein CV, Capelluto DG. A rapid procedure to isolate isotopically labeled peptides for NMR studies: application to the Disabled-2 sulfatide-binding motif. J Pept Sci. 2014;20:216–222.  http://www.ncbi.nlm.nih.gov/pubmed/24470337

2013

Larion S, Caballes FR, Hwang SI, et al. Circadian rhythms in acute intermittent porphyria--a pilot study. Eur J Clin Invest. 2013;43:727–739.  http://www.ncbi.nlm.nih.gov/pubmed/23650938

Xiao S, Finkielstein CV, Capelluto DG. The enigmatic role of sulfatides: new insights into cellular functions and mechanisms of protein recognition. Adv Exp Med Biol. 2013;991:27–40.  http://www.ncbi.nlm.nih.gov/pubmed/23775689

2012

Xiao S, Charonko JJ, Fu X, et al. Structure, sulfatide binding properties, and inhibition of platelet aggregation by a disabled-2 protein-derived peptide. J Biol Chem. 2012;287:37691–37702.  http://www.ncbi.nlm.nih.gov/pubmed/22977233

2011

Alajlouni R, Drahos KE, Finkielstein CV, Capelluto DG. Lipid-mediated membrane binding properties of Disabled-2. Biochim Biophys Acta. 2011;1808:2734–2744.  http://www.ncbi.nlm.nih.gov/pubmed/21820403

Cordoba L, Huang YW, Opriessnig T, et al. Three amino acid mutations (F51L, T59A, and S390L) in the capsid protein of the hepatitis E virus collectively contribute to virus attenuation. J Virol. 2011;85:5338–5349.  http://www.ncbi.nlm.nih.gov/pubmed/21450834

Gotoh T, Villa LM, Capelluto DG, Finkielstein CV. Regulatory pathways coordinating cell cycle progression in early Xenopus development. Results Probl Cell Differ. 2011;53:171–199.  http://www.ncbi.nlm.nih.gov/pubmed/21630146

Howells CC, Baumann WT, Samuels DC, Finkielstein CV. The Bcl-2-associated death promoter (BAD) lowers the threshold at which the Bcl-2-interacting domain death agonist (BID) triggers mitochondria disintegration. J Theor Biol. 2011;271:114–123.  http://www.ncbi.nlm.nih.gov/pubmed/21130780

Welsh JD, Charonko JJ, Salmanzadeh A, et al. Disabled-2 modulates homotypic and heterotypic platelet interactions by binding to sulfatides. Br J Haematol. 2011;154:122–133.  http://www.ncbi.nlm.nih.gov/pubmed/21539534

2010

Allen WJ, Capelluto DG, Finkielstein CV, Bevan DR. Modeling the relationship between the p53 C-terminal domain and its binding partners using molecular dynamics. J Phys Chem B. 2010;114:13201–13213.  http://www.ncbi.nlm.nih.gov/pubmed/20873738

Armenta JM, Perez M, Yang X, et al. Fast proteomic protocol for biomarker fingerprinting in cancerous cells. J Chromatogr A. 2010;1217:2862–2870.  http://www.ncbi.nlm.nih.gov/pubmed/20307887

Azurmendi HF, Mitra S, Ayala I, Li L, Finkielstein CV, Capelluto DG. Backbone (1)H, (15)N, and (13)C resonance assignments and secondary structure of the Tollip CUE domain. Mol Cells. 2010;30:581–585.  http://www.ncbi.nlm.nih.gov/pubmed/20957454

Dong J, Mury SP, Drahos KE, Moscovitch M, Zia RK, Finkielstein CV. Shorter exposures to harder X-rays trigger early apoptotic events in Xenopus laevis embryos. PLoS One. 2010;5:e8970.  http://www.ncbi.nlm.nih.gov/pubmed/20126466

2009

Drahos KE, Welsh JD, Finkielstein CV, Capelluto DG. Sulfatides partition disabled-2 in response to platelet activation. PLoS One. 2009;4:e8007.  http://www.ncbi.nlm.nih.gov/pubmed/19956625

2008

Sweede M, Ankem G, Chutvirasakul B, et al. Structural and membrane binding properties of the prickle PET domain. Biochemistry. 2008;47:13524–13536.  http://www.ncbi.nlm.nih.gov/pubmed/19053268

Yang J, Kim KD, Lucas A, et al. A novel heme-regulatory motif mediates heme-dependent degradation of the circadian factor period 2. Mol Cell Biol. 2008;28:4697–4711.  http://www.ncbi.nlm.nih.gov/pubmed/18505821

2007

Wroble BN, Finkielstein CV, Sible JC. Wee1 kinase alters cyclin E/Cdk2 and promotes apoptosis during the early embryonic development of Xenopus laevis. BMC Dev Biol. 2007;7:119.  http://www.ncbi.nlm.nih.gov/pubmed/17961226

2006

Finkielstein CV, Overduin M, Capelluto DG. Cell migration and signaling specificity is determined by the phosphatidylserine recognition motif of Rac1. J Biol Chem. 2006;281:27317–27326.  http://www.ncbi.nlm.nih.gov/pubmed/16861229

2004

Bemis L, Chan DA, Finkielstein CV, et al. Distinct aerobic and hypoxic mechanisms of HIF-alpha regulation by CSN5. Genes Dev. 2004;18:739–744.  http://www.ncbi.nlm.nih.gov/pubmed/15082527

Gai D, Li D, Finkielstein CV, et al. Insights into the oligomeric states, conformational changes, and helicase activities of SV40 large tumor antigen. J Biol Chem. 2004;279:38952–38959.  http://www.ncbi.nlm.nih.gov/pubmed/15247252

Gai D, Zhao R, Li D, Finkielstein CV, Chen XS. Mechanisms of conformational change for a replicative hexameric helicase of SV40 large tumor antigen. Cell. 2004;119:47–60.  http://www.ncbi.nlm.nih.gov/pubmed/15454080

2002

Capelluto DG, Kutateladze TG, Habas R, Finkielstein CV, He X, Overduin M. The DIX domain targets dishevelled to actin stress fibres and vesicular membranes. Nature. 2002;419:726–729.  http://www.ncbi.nlm.nih.gov/pubmed/12384700

Cymeryng CB, Lotito SP, Colonna C, et al. Expression of nitric oxide synthases in rat adrenal zona fasciculata cells. Endocrinology. 2002;143:1235–1242.  http://www.ncbi.nlm.nih.gov/pubmed/11897679

Finkielstein CV, Chen LG, Maller JL. A role for G1/S cyclin-dependent protein kinases in the apoptotic response to ionizing radiation. J Biol Chem. 2002;277:38476–38485.  http://www.ncbi.nlm.nih.gov/pubmed/12176996

2001

Finkielstein CV, Lewellyn AL, Maller JL. The midblastula transition in Xenopus embryos activates multiple pathways to prevent apoptosis in response to DNA damage. Proc Natl Acad Sci U S A. 2001;98:1006–1011.  http://www.ncbi.nlm.nih.gov/pubmed/11158585

Maller JL, Gross SD, Schwab MS, Finkielstein CV, Taieb FE, Qian YW. Cell cycle transitions in early Xenopus development. Novartis Found Symp. 2001;237:58–73; discussion 73–8.  http://www.ncbi.nlm.nih.gov/pubmed/11444050

1999

Neuman I, Lisdero C, Finkielstein C, et al. Activation of a thioesterase specific for very-long-chain fatty acids by adrenergic agonists in perfused hearts. Biochim Biophys Acta. 1999;1451:101–108.  http://www.ncbi.nlm.nih.gov/pubmed/10446392

1998

Finkielstein C, Maloberti P, Mendez CF, et al. An adrenocorticotropin-regulated phosphoprotein intermediary in steroid synthesis is similar to an acyl-CoA thioesterase enzyme. Eur J Biochem. 1998;256:60–66.  http://www.ncbi.nlm.nih.gov/pubmed/9746346

Finkielstein CV, Maloberti P, Mendez CF, Podesta EJ. A novel arachidonic acid-related thioesterase involved in acute steroidogenesis. Endocr Res. 1998;24:363–371.  http://www.ncbi.nlm.nih.gov/pubmed/9888508

1997

Mele PG, Dada LA, Paz C, et al. Involvement of arachidonic acid and the lipoxygenase pathway in mediating luteinizing hormone-induced testosterone synthesis in rat Leydig cells. Endocr Res. 1997;23:15–26.  http://www.ncbi.nlm.nih.gov/pubmed/9187535

1996

Dada L, Cornejo Maciel F, Neuman I, et al. Cytosolic and mitochondrial proteins as possible targets of cycloheximide effect on adrenal steroidogenesis. Endocr Res. 1996;22:533–539.  http://www.ncbi.nlm.nih.gov/pubmed/8969907

Finkielstein C, Cymeryng C, Paz C, et al. Characterization of the cDNA corresponding to a phosphoprotein (p43) intermediary in the action of ACTH. Endocr Res. 1996;22:521–532.  http://www.ncbi.nlm.nih.gov/pubmed/8969906

Mele PG, Dada LA, Paz C, et al. Site of action of proteinases in the activation of steroidogenesis in rat adrenal gland. Biochim Biophys Acta. 1996;1310:260–268.  http://www.ncbi.nlm.nih.gov/pubmed/8599603

1995

Cymeryng CB, Paz C, Dada L, et al. ACTH-dependent proteolytic activity of a novel phosphoprotein (p43) intermediary in the activation of phospholipase A2 and steroidogenesis. Endocr Res. 1995;21:281–288.  http://www.ncbi.nlm.nih.gov/pubmed/7588391

1994

Paz C, Dada LA, Cornejo Maciel MF, et al. Purification of a novel 43-kDa protein (p43) intermediary in the activation of steroidogenesis from rat adrenal gland. Eur J Biochem. 1994;224:709–716.  http://www.ncbi.nlm.nih.gov/pubmed/7925388