Protein Kinase Cδ Is Essential to Maintain <i>CIITA</i> Gene Expression in B Cells

Kwon, Myung Ja; Soh, Jae-Won; Chang, Cheong Hee

doi:10.4049/jimmunol.177.2.950

Cited by 13 publications

(9 citation statements)

References 51 publications

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“…This transient PKC activation pattern is consistent with other studies reporting that higher PMA concentrations and prolonged exposure to PMA could cause PKC depletion (Butler et al, 1991;Chang et al, 2002). Similar findings showed that highest PKC induction in B cells was obtained with 20 nM PMA and 6 hours incubation time (Kwon et al, 2006).…”

Section: Resultssupporting

confidence: 92%

Suppressive Effect of Maslinic Acid on PMA-induced Protein Kinase C in Human B-Lymphoblastoid Cells

Lim

Yew

Yap

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Section: Resultssupporting

confidence: 92%

Suppressive Effect of Maslinic Acid on PMA-induced Protein Kinase C in Human B-Lymphoblastoid Cells

Lim

Yew

Yap

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…In a subset of these specific circumstances, the activation of the PKCdelta isoform has been linked to the CREB-dependent transcription of cellular genes (6,30,62). CREB Ser133 is a substrate for multiple cellular kinases that include PKC, PKA, calcium-calmodulin-dependent kinases II and IV, MSK-1, PP90 rsk , and MAP-KAP2 (35).…”

Section: Discussionmentioning

confidence: 99%

Phorbol Ester-Induced Human Cytomegalovirus Major Immediate-Early (MIE) Enhancer Activation through PKC-Delta, CREB, and NF-κB Desilences MIE Gene Expression in Quiescently Infected Human Pluripotent NTera2 Cells

Liu

Yuan

et al. 2010

J Virol

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Novel strategies to mitigate the disease burden resulting from human cytomegalovirus (CMV) (HCMV) reactivation are needed. Knowledge about the ways in which HCMV major immediate-early (MIE) gene expression breaks silence from latency to start the viral replicative cycle has the potential to inform the development of new therapies to preempt viral replication. However, the molecular mechanisms that regulate the switch from HCMV MIE gene silence to activation are poorly understood.The expression of viral MIE genes is required to initiate the productive life cycles of human and animal CMV species, whereas expression is greatly restricted or absent during the latency of these viruses (39,52,53,57). The 550-bp MIE enhancer is the vital regulatory center for the transcriptional activation of the MIE gene locus (39). The enhancer's function is attributed to assorted cis-acting elements that are consensus binding sites for different specific cellular transcription factors (9,22,31,37); several types of cis-acting elements are repeated. Signaling networks relay and integrate information from the cell, the virus, and the extracellular environment to dynamically modulate the functional activities of these cellular transcription factors (9, 24). The composite configuration of the specific cis-acting elements in the HCMV MIE enhancer differs greatly from that of evolutionarily distant cytomegalovirus relatives (39). This may explain why the replacement of this enhancer with the MIE enhancer from murine CMV (MCMV) renders HCMV poorly competent at executing both MIE gene expression and viral genome replication in lytically infected cells (21).HCMV infection of human pluripotent embryonal NTera2/D1 (NT2) cells is a tractable model with which to molecularly characterize the regulatory mechanisms that break HCMV MIE gene expression silence in a setting of viral quiescence (25, 36). These cells become either neurons and astrocytes after treatment with retinoic acid (RA) (2, 3) or epithelial and smooth muscle-like cells after treatment with bone morphogenetic protein 2 (10). Keeping NT2 cells in an undifferentiated state, partly by propagation under progenitor cell growth conditions (36), promotes quiescent HCMV infection and results in greater than 98% of NT2 nuclei containing HCMV pp65 at 1 h postinfection (p.i.) with a multiplicity of infection (MOI) of 3 to 5 (25) and approximately 3 HCMV genome equivalents per nucleus at 24 h p.i. with an MOI of 10 (38). At 48 h p.i., the NT2 cells contain a subset of nonreplicating HCMV genomes having a DNA structure of covalently closed circles with superhelical twists (36).

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“…One mode by which kinases regulate CIITA is by controlling expression of the CIITA gene. Interferon-␥ activates PKC, thereby causing interferon regulatory factor-1 and CREB to activate CIITA expression through its type IV promoter, resulting in MHC class II gene expression (50,53,66). Likewise, chemical inhibition of PKC blocks CIITA gene expression (67).…”

Section: Discussionmentioning

confidence: 99%

Mitogen-activated Protein Kinase ERK1/2 Regulates the Class II Transactivator

Voong

Slater

Kratovac

et al. 2008

Journal of Biological Chemistry

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The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translational events, including GTP binding, ubiquitination, and dimerization. However, the role of phosphorylation is less clearly defined as are the consequences of phosphorylation on CIITA activity and the identity of the kinases involved. In this study we show that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) interact directly with CIITA, targeting serine residues in the amino terminus of the protein, including serine 288. Inhibition of this phosphorylation by dominant-negative forms of ERK or by treatment of cells with the ERK inhibitor PD98059 resulted in the increase in CIITA-mediated gene expression from a class II promoter, enhanced the nuclear concentration of CIITA, and impaired its ability to bind to the nuclear export factor, CRM1. In contrast, inhibition of ERK1/2 activity had little effect on serine-to-alanine mutant forms of CIITA. These data suggest a model whereby ERK1/2-mediated phosphorylation of CIITA down-regulates CIITA activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation.The class II transactivator CIITA 2 plays a critical role in initiating an immune response by activating the expression of major histocompatibility (MHC) class II genes and associated molecules (2-6). MHC II glycoproteins are necessary for the presentation of antigenic peptides to CD4 ϩ T lymphocytes and the subsequent initiation and propagation of CD4 ϩ T cell-mediated immune responses and are involved in the development and maintenance of homeostasis of the CD4 ϩ T cell population. Although constitutive expression of MHC class II genes is primarily restricted to a specific subset of antigen-presenting cells that include B cells and dendritic cells, expression is inducible in a variety of other cell types and tissues by cytokines such as interferon-␥ and tumor necrosis factor-␣ (1). Both constitutive and inducible expression of MHC II and other related genes are contingent upon the activation of CIITA (7,8). Loss of a functional CIITA protein results in an immunodeficiency called bare lymphocyte syndrome, which is characterized by a complete absence of MHC class II-mediated antigen presentation. Patients with this disease suffer from recurrent infections due to opportunistic infections and, ultimately, death in early childhood (9 -11).CIITA is a protein of 1130 amino acids that does not bind directly to DNA. Instead, it regulates gene expression by interacting with other transcription factors and chromatin-remodeling proteins at the W/X/Y regulatory elements in the promoter regions of class II genes (for review, see Refs. 12-17). Nuclear factors binding to CIITA include the regulatory factor X (RFX) complex (RFX5, RFXAP, RFXANK/RFX-B) (18) and nuc...

show abstract

Protein Kinase Cδ Is Essential to Maintain CIITA Gene Expression in B Cells

Cited by 13 publications

References 51 publications

Suppressive Effect of Maslinic Acid on PMA-induced Protein Kinase C in Human B-Lymphoblastoid Cells

Suppressive Effect of Maslinic Acid on PMA-induced Protein Kinase C in Human B-Lymphoblastoid Cells

Phorbol Ester-Induced Human Cytomegalovirus Major Immediate-Early (MIE) Enhancer Activation through PKC-Delta, CREB, and NF-κB Desilences MIE Gene Expression in Quiescently Infected Human Pluripotent NTera2 Cells

Mitogen-activated Protein Kinase ERK1/2 Regulates the Class II Transactivator

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