Loma Linda University

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Kimberly Payne, PhD
Director, Translational Reserach, Basic Sciences
School of Medicine
Associate Professor, Pathology and Human Anatomy
School of Medicine
Associate Professor, Medicine
School of Medicine
Associate Professor, Pediatrics
School of Medicine
Member, Anatomy, SM, Faculty of Graduate Studies
Publications    Scholarly Journals--Published
  • Emilie E. Vomhof-DeKrey, Ashley R. Sandy, Jarrett J. Failing, Rebecca J. Hermann, Scott A. Hoselton, Jane M. Schuh, Abby J. Weldon,  Kimberly J. Payne and Glenn P. Dorsam. "Radical Reversal of Vasoactive Intestinal Peptide Receptors During Early Lymphopoiesis."  Peptides. 2011 Oct;32(10):2058-66. ( 10/2011 - 8/2011 )
    Successful thymocyte maturation is essential for normal, peripheral T cell function. Vasoactive intestinal peptide (VIP) is a neuropeptide which is highly expressed in the thymus that has been shown to modulate thymocyte development. VIP predominantly binds two G protein coupled receptors, termed vasoactive intestinal peptide receptor 1 (VPAC1) and VPAC2, but their expression profiles in CD4(-)/CD8(-) (double negative, DN) thymocyte subsets, termed DN1-4, have yet to be identified. We hypothesized that a high VPAC1:VPAC2 ratio in the earliest thymocyte progenitors (ETP cells) would be reversed during early lymphopoiesis as observed in activated, peripheral Th(2) cells, as the thymus is rich in Th(2) cytokines. In support of this hypothesis, high VPAC1 mRNA levels decreased 1000-fold, accompanied with a simultaneous increase in VPAC2 mRNA expression during early thymocyte progenitor (ETP/DN1)→DN3 differentiation. Moreover, arrested DN3 cells derived from an Ikaros null mouse (JE-131 cells) failed to completely reverse the VIP receptor ratio compared to wild type DN3 thymocytes. Surprisingly, VPAC2(-/-) mice did not show significant changes in relative thymocyte subset numbers. These data support the notion that both VPAC1 and VPAC2 receptors are dynamically regulated by Ikaros, a master transcriptional regulator for thymocyte differentiation, during early thymic development. Moreover, high VPAC1 mRNA is a novel marker for the ETP population making it enticing to speculate that the chemotactic VIP/VPAC1 signaling axis may play a role in thymocyte movement. Also, despite the results that VPAC2 deficiency did not affect thymic subset numbers, future studies are necessary to determine whether downstream T cell phenotypic changes manifest themselves, such as a propensity for a Th(1) versus Th(2) polarization.
  • Sinisa Dovat, Chunhua Song, Kimberly J. Payne, and Zhanjun Li. "Ikaros, CK2 Kinase, and the Road to Leukemia." Molecular and Cellular Biochemistry. Mol Cell Biochem. 2011 Oct;356(1-2):201-7. ( 7/2011 )
    Ikaros encodes a zinc finger protein that is essential for hematopoiesis and that acts as a tumor suppressor in leukemia. Ikaros function depends on its ability to localize to pericentromeric-heterochromatin (PC-HC). Ikaros protein binds to the upstream regulatory elements of target genes, aids in their recruitment to PC-HC, and regulates their transcription via chromatin remodeling. We identified four novel Ikaros phosphorylation sites that are phosphorylated by CK2 kinase. Using Ikaros phosphomimetic and phosphoresistant mutants of the CK2 phosphorylation sites, we demonstrate that (1) CK2-mediated phosphorylation inhibits Ikaros'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' localization to PC-HC; (2) dephosphorylation of Ikaros at CK2 sites increases its binding to the promoter of the terminal deoxynucleotidetransferase (TdT) gene, leading to TdT repression during thymocyte differentiation; and (3) hyperphosphorylation of Ikaros promotes its degradation by the ubiquitin/proteasome pathway. We show that Ikaros is dephosphorylated by Protein Phosphatase 1 (PP1) via interaction at a consensus PP1-binding motif, RVXF. Point mutations that abolish Ikaros-PP1 interaction result in functional changes in DNA-binding affinity and subcellular localization, similar to those observed in hyperphosphorylated Ikaros and/or Ikaros phosphomimetic mutants. Phosphoresistant Ikaros mutations at CK2 sites restored Ikaros'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' DNA-binding activity and localization to PC-HC and prevented accelerated Ikaros degradation. These results demonstrate the role of CK2 kinase in lymphocyte differentiation and in regulation of Ikaros'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''' function, and suggest that CK2 promotes leukemogenesis by inhibiting the tumor suppressor activity of Ikaros. We propose a model whereby a balance between CK2 kinase and PP1 phosphatase is essential for normal lymphocyte differentiation and for the prevention of malignant transformation.
  • Olivia L. Francis, Jonathon L. Payne, Rui-Jun Su, and Kimberly J. Payne. "Regulator of Myeloid Differentiation and Function: The Secret Life of Ikaros" World J. Biol. Chem. 2011 Jun 26;2(6):119-25. ( 6/2011 )
    Ikaros (also known as Lyf-1) was initially described as a lymphoid-specific transcription factor. Although Ikaros has been shown to regulate hematopoietic stem cell renewal, as well as the development and function of cells from multiple hematopoietic lineages, including the myeloid lineage, Ikaros has primarily been studied in context of lymphoid development and malignancy. This review focuses on the role of Ikaros in myeloid cells. We address the importance of post-transcriptional regulation of Ikaros function; the emerging role of Ikaros in myeloid malignancy; Ikaros as a regulator of myeloid differentiation and function; and the selective expression of Ikaros isoform-x in cells with myeloid potential. We highlight the challenges of dissecting Ikaros function in lineage commitment decisions among lymphoid-myeloid progenitors that have emerged as a major myeloid differentiation pathway in recent studies, which leads to reconstruction of the traditional map of murine and human hematopoiesis.
  • Padilla A, Descorbeth M, Almeyda AL, Payne K, De Leon M. "Hyperglycemia magnifies Schwann cell dysfunction and cell death triggered by PA-induce lipotoxicity." Brain Research. 2011 Jan 25;1370:64-79. ( 1/2011 )
    Lipid overload resulting in lipotoxicity is prominent in a number of chronic diseases and has been associated with cellular dysfunction and cell death. This study characterizes palmitic acid-induced lipotoxicity (PA-LTx) in Schwann cell cultures grown in normal and high glucose concentrations. The study shows for the first time that Schwann cell (SC) cultures exposed to elevated levels of PA exhibit a dose- and time-dependent loss in cell viability. Hoescht and Annexin V/7AAD staining confirmed cell death through apoptosis and the lipotoxic effect was more dramatic in SC cultures grown under high glucose conditions. The first indication of cellular dysfunction in treated SC cultures was a decrease in Ca(++) levels in the endoplasmic reticulum (ER, [Ca(++)](ER)) observed five minutes following the initial challenge with PA. This decrease in [Ca(++) ](ER) was followed by a significant increase in the expression of ER stress signature genes CHOP, Xbp1 and GRP78. The early ER stress response induced by PA-LTx was followed by a strong mitochondrial membrane depolarization. Flow cytometry using 2'''', 7''''-dichlorodihydrofluorescein diacetate (H(2)DCFDA) showed an increase in oxidative stress within three to six hours after PA treatment. Treatment of cultures undergoing PA-LTx with the calcium chelator BAPTA-AM and the anti-oxidant MCI-186 significantly reversed the lipotoxic effect by decreasing the generation of ROS and significantly increasing cell viability. We conclude that lipotoxicity in Schwann cells results in cellular dysfunction and cell death that involves a robust ER stress response, mitochondrial dysfunction and an augmented state of cellular oxidative stress (ASCOS).
  • Dovat, S. and Payne K.J. "Tumor Suppression in T Cell Leukemia–The Role of Ikaros."  Leuk Res. 2010. 34(4)):416-7. ( 4/2010 )
  • Popescu M, Gurel Z, Ronni T, Song  C,  Hung K, Payne KJ, and Dovat S. "Ikaros Stability and Pericentromeric Localization are Regulated by Protein Phosphatase 1." J Biol Chem. 2009, 284(20):13869-80. ( 5/2009 )
    Ikaros encodes a zinc finger protein that is involved in gene regulation and chromatin remodeling. The majority of Ikaros localizes at pericentromeric heterochromatin (PC-HC) where it regulates expression of target genes. Ikaros function is controlled by posttranslational modification. Phosphorylation of Ikaros by CK2 kinase determines its ability to bind DNA and exert cell cycle control, as well as its subcellular localization. We report that Ikaros interacts with Protein Phosphatase 1 (PP1) via a conserved PP1-binding motif, RVXF, in the C-terminal end of the Ikaros protein. Point mutations of the RVXF motif abolish Ikaros-PP1 interaction and result in decreased DNA-binding, an inability to localize to PC-HC, and rapid degradation of the Ikaros protein. The introduction of alanine mutations at CK2-phosphorylated residues increases the half-life of the PP1-nonbinding Ikaros mutant. This suggests that dephosphorylation of these sites by PP1 stabilizes the Ikaros protein, and prevents its degradation. In the nucleus, Ikaros forms complexes with ubiquitin, providing evidence that Ikaros degradation involves the ubiquitin/proteasome pathway. In vivo, Ikaros can target PP1 to the nucleus and a fraction of PP1 co-localizes with Ikaros at PC-HC. These data suggest a novel function for the Ikaros protein–the targeting of PP1 to PC-HC and other chromatin structures. We propose a model whereby the function of Ikaros is controlled by the CK2 and PP1 pathways and that a balance between these two signal transduction pathways is essential for normal cellular function and for the prevention of malignant transformation.
  • Parrish YK, Baez I, Milford T-A, Benitez A, Galloway N, Willeman-Rogerio J, Sahakian E,  Kagoda M, Huang G, Hao QL, Sevilla Y, Barsky LW, Zielinska E, Price MA, Wall NR, Dovat S, and Payne KJ.  "IL-7 Dependence in Human B Lymphopoiesis Increases During Progression of Ontogeny from  Cord Blood to Bone Marrow." J Immunol. 2009 Apr 1;182(7):4255-66. ( 4/2009 )
    Abstract IL-7 is critical for B cell production in adult mice, however its role in human B lymphopoiesis is controversial. One challenge was the inability to differentiate human cord blood (CB) or adult bone marrow (BM) hematopoietic stem cells (HSCs) without murine stroma.  Here, we examine the role of IL-7 in human B cell development using a novel, human-only model based on co-culturing human HSCs on primary human BM stroma. In this model, IL-7 increases human B cell production by >60-fold from both CB and adult BM HSCs. IL-7-induced increases are dose-dependent and specific to CD19+ cells. STAT5 phosphorylation and expression of the Ki-67 proliferation antigen, indicate that IL-7 acts directly on CD19+ cells to increase proliferation at the CD34+ and CD34– pro-B cell stages. Without IL-7, HSCS in CB, but not BM give rise to a small but consistent population of CD19LO B lineage cells that express EBF and PAX-5 and respond to subsequent IL-7 stimulation. Flt3 ligand, but not thymic stromal-derived lymhopoietin (TSLP), was required for the IL-7-independent production of human B lineage cells. As compared to CB,  adult BM shows a reduction of in vitro generative capacity that is progressively more profound in developmentally sequential populations, resulting in a ~50-fold reduction in IL-7-dependent B lineage generative capacity. These data provide evidence that IL-7 is essential for human B cell production from adult BM and that IL-7-induced expansion of the pro-B compartment is increasingly critical for human B cell production during the progression of ontogeny.
  • Gurel Z, Ronni T, Ho S, Kuchar J, Payne KJ, Turk C, and Dovat S. "Recruitment of Ikaros to Pericentromeric Heterochromatin is Regulated by Phosphorylation," J Biol Chem. 283(13):8291-300, 2008. ( 3/2008 ) Link...
    Ikaros encodes a zinc finger protein that is involved in heritable gene silencing.  In hematopoietic cells, Ikaros localizes to pericentromeric heterochromatin (PC-HC) where it recruits its target genes, resulting in their activation or repression via chromatin remodeling. The function of Ikaros is controlled by post-translational modifications. CK2 kinase has been shown to phosphorylate Ikaros at its C-terminus, affecting cell cycle progression. Using in vivo labeling of murine thymocytes followed by phosphopeptide mapping, we identified four novel Ikaros phosphorylation sites. Functional analysis of phosphomimetic mutants showed that the phosphorylation of individual amino acids determines the affinity of Ikaros toward probes derived from PC-HC. In vivo experiments demonstrated that targeting of Ikaros to PC-HC is regulated by phosphorylation. The ability of Ikaros to bind the upstream regulatory elements of its known target gene–terminal deoxynucleotidetransferase (TdT)–was decreased by phosphorylation of two amino acids. In thymocytes, Ikaros acts as a repressor of the TdT gene.  Induction of differentiation of thymocytes with PMA plus ionomycin results in transcriptional repression of TdT expression. This process has been associated with increased binding of Ikaros to the upstream regulatory element of TdT. Phosphopeptide analysis of in vivo-labeled thymocytes revealed that Ikaros undergoes dephosphorylation during induction of thymocyte differentiation and that dephosphorylation is responsible for increased DNA-binding affinity of Ikaros toward the TdT promoter. We propose a model whereby reversible phosphorylation of Ikaros at specific amino acids controls the subcellular localization of Ikaros, as well as its ability to regulate TdT expression during thymocyte differentiation.
  • Luo P, Wang A, Payne KJ, Peng H, Wang J-G, Parrish YK, Rogerio JW, Triche TJ, He Q, and Wu L.. "Intrinsic RAR{alpha}-CAK Signaling Involves Coordination of The Restricted Proliferation and Granulocytic Differentiation of Human Hematopoietic Stem Cells." Stem Cells.  2007 Oct;25(10):2628-37. ( 7/2007 ) Link...
    Little is known about the mechanisms by which retinoic acid receptor alpha (RARalpha) mediates the effects of retinoic acid (RA) to coordinate granulocytic proliferation/differentiation (P/D) transition. Cyclin-dependent kinase-activating kinase (CAK) complex, whose activity in phosphorylation of RARalpha is determined by its targeting subunit ménage à trois 1 (MAT1), regulates G1 exit, a cell cycle stage when cells commonly commit to proliferation or to differentiation. We previously found that, in myeloid leukemia cells, the lack of RA-induced RARalpha-CAK dissociation and MAT1 degradation suppresses cell differentiation by inhibiting CAK-dependent G1 exit and sustaining CAK hyperphosphorylation of RARalpha. This contrasts with our recent findings about the P/D transition in normal primitive hematopoietic cells, where MAT1 degradation proceeds intrinsically together with granulocytic development, in accord with dynamic expression of aldehyde dehydrogenases (ALDH) 1A1 and 1B1, which catalyze RA synthesis. Blocking ALDH activity inhibits MAT1 degradation and granulocytic differentiation, while loss of RARalpha phosphorylation by CAK induces RA-target gene expression and granulocytic differentiation. These studies suggest that the subversion of RARalpha-CAK signaling during normal granulopoiesis is crucial to myeloid leukemogenesis and challenges the current paradigm that RA induces cell differentiation solely by transactivating target genes.
  • Payne KJ and Crooks GM. "Immune-Cell Lineage Commitment: Translation from Mice to Humans." Immunity. 26.6 (2007): 674-677. ( 6/2007 ) Link...
    Much of the current understanding in hematopoietic stem cell differentiation into immune-cell lineages comes from mouse studies, but how well does it translate to the human system?
  • Ronni T, Payne KJ, Ho S, Bradley MN, Dorsam G and Dovat S. . "Human Ikaros Function in Activated T Cells is Regulated by Coordinated Expression of Its Largest Isoforms." J. Biol Chem. 282.4 (2007): 2538-2547. ( 1/2007 ) Link...
    The Ikaros gene is alternately spliced to generate multiple zinc finger proteins involved in gene regulation and chromatin remodeling. Whereas murine studies have provided important information regarding the role of Ikaros in the mouse, little is known of Ikaros function in human. We report functional analyses of the two largest human Ikaros (hIK) isoforms, hIK-VI and hIK-H, in T cells. Abundant expression of hIK-H, the largest described isoform, is restricted to human hematopoietic cells. We find that the DNA binding affinity of hIK-H differs from that of hIK-VI. Co-expression of hIk-H with hIk-VI alters the ability of Ikaros complexes to bind DNA motifs found in pericentromeric heterochromatin (PC-HC). In the nucleus, hIK-VI is localized solely in PC-HC, whereas the hIK-H protein exhibits dual centromeric and non-centromeric localization. Mutational analysis defined the amino acids responsible for the distinct DNA binding ability of hIK-H, as well as the sequence required for the specific subcellular localization of this isoform. In proliferating cells, the binding of hIK-H to the upstream regulatory region of known Ikaros target genes correlates with their positive regulation by Ikaros. Results suggest that expression of hIK-H protein restricts affinity of Ikaros protein complexes toward specific PC-HC repeats. We propose a model, whereby the binding of hIK-H-deficient Ikaros complexes to the regulatory sequence of target genes would recruit these genes to the restrictive pericentromeric compartment, resulting in their repression. The presence of hIK-H in the Ikaros complex would alter its affinity for PC-HC, leading to chromatin remodeling and activation of target genes.
  Scholarly Journals--Accepted
  • Odumosu O, Payne K, Baez I, Jutzy J, Wall N, Langridge W. "Suppression of Dendritic Cell Activation by Diabetes Autoantigens linked to the Cholera Toxin B Subunit." Immunnobiology. 216(4):447-56. ( 9/2010 )
    Antigen presenting cells, specifically dendritic cells (DCs) are a focal point in the delicate balance between T cell tolerance and immune responses contributing to the onset of type I diabetes (T1D). Weak adjuvant proteins like the cholera toxin B subunit when linked to autoantigens may sufficiently alter the balance of this initial immune response to suppress the development of autoimmunity. To assess adjuvant enhancement of autoantigen mediated immune suppression of Type 1 diabetes, we examined the cholera toxin B subunit (CTB)-proinsulin fusion protein (CTB-INS) activation of immature dendritic cells (iDC) at the earliest detectable stage of the human immune response. In this study, Incubation of human umbilical cord blood monocyte-derived immature DCs with CTB-INS autoantigen fusion protein increased the surface membrane expression of DC Toll-like receptor (TLR-2) while no significant upregulation in TLR-4 expression was detected. Inoculation of iDCs with CTB stimulated the biosynthesis of both CD86 and CD83 co-stimulatory factors demonstrating an immunostimulatory role for CTB in both DC activation and maturation. In contrast, incubation of iDCs with proinsulin partially suppressed CD86 co-stimulatory factor mediated DC activation, while incubation of iDCs with CTB-INS fusion protein completely suppressed iDC biosynthesis of both CD86 and CD83 costimulatory factors. The incubation of iDCs with increasing amounts of insulin did not increase the level of immune suppression but rather activated DC maturation by stimulating increased biosynthesis of both CD86 and CD83 costimulatory factors. Inoculation of iDCs with CTB-INS fusion protein dramatically increased secretion of the immunosuppressive cytokine IL-10 and suppressed synthesis of the pro-inflammatory cytokine IL12/23 p40 subunit protein suggesting that linkage of CTB to insulin (INS) may play an important role in mediating DC guidance of cognate naïve Th0 cell development into immunosuppressive T lymphocytes. Taken together, the experimental data suggests Toll like receptor 2 (TLR-2) plays a dominant role in CTB mediated INS inhibition of DC induced type 1 diabetes onset in human Type 1 diabetes autoimmunity. Further, fusion of CTB to the autoantigen was found to be essential for enhancement of immune suppression as co-delivery of CTB and insulin did not significantly inhibit DC costimulatory factor biosynthesis. The experimental data presented supports the hypotheses that adjuvant enhancement of autoantigen mediated suppression of islet beta cell inflammation is dependent on CTB stimulation of dendritic cell TLR2 receptor activation and co-processing of both CTB and the autoantigen in the same dendritic cell.
  Books and Chapters
  • Sinisa Dovat and Kimberly J. Payne "Chapter 6: Ikaros in T-Cell Leukemia." In T-Cell Leukemia  (Babusikova, Dovat S and Payne KJ Eds).. Intech – Open Access Publishers ISBN 978-953-307-400-9 ( 9/2011 )