Chromatinized Protein Kinase C-theta: Can It Escape the Clutches of NF-kB?

Elissa Sutcliffe, Jasmine Li, Anjum Zafar, Kristine Hardy, Reena Ghildyal, Nicole Norris, Chloe (Pek Siew) Lim, Peter Milburn, Marco Casarotto, Gareth Denyer, Sudha Rao

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

We recently provided the first description of a nuclear mechanism used by Protein Kinase C-theta (PKC-θ) to mediate T cell gene expression. In this mode, PKC-θ tethers to chromatin to form an active nuclear complex by interacting with proteins including RNA polymerase II, the histone kinase MSK-1, the demethylase LSD1, and the adaptor molecule 14-3-3ζ at regulatory regions of inducible immune response genes. Moreover, our genome-wide analysis identified many novel PKC-θ target genes and microRNAs implicated in T cell development, differentiation, apoptosis, and proliferation. We have expanded our ChIP-on-chip analysis and have now identified a transcription factor motif containing NF-κB binding sites that may facilitate recruitment of PKC-θ to chromatin at coding genes. Furthermore, NF-κB association with chromatin appears to be a prerequisite for the assembly of the PKC-θ active complex. In contrast, a distinct NF-κB-containing module appears to operate at PKC-θ targeted microRNA genes, and here NF-κB negatively regulates microRNA gene transcription. Our efforts are also focusing on distinguishing between the nuclear and cytoplasmic functions of PKCs to ascertain how these kinases may synergize their roles as both cytoplasmic signaling proteins and their functions on the chromatin template, together enabling rapid induction of eukaryotic genes. We have identified an alternative sequence within PKC-θ that appears to be important for nuclear translocation of this kinase. Understanding the molecular mechanisms used by signal transduction kinases to elicit specific and distinct transcriptional programs in T cells will enable scientists to refine current therapeutic strategies for autoimmune diseases and cancer.
Original languageEnglish
Pages (from-to)260-273
Number of pages14
JournalFrontiers in Immunology
Volume3
Issue numberE
DOIs
Publication statusPublished - 2012

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NF-kappa B
Protein Kinase C
Chromatin
MicroRNAs
Genes
Phosphotransferases
T-Lymphocytes
Protamine Kinase
RNA Polymerase II
Nucleic Acid Regulatory Sequences
Autoimmune Diseases
Cell Differentiation
Signal Transduction
Proteins
Transcription Factors
Binding Sites
Genome
Apoptosis
Gene Expression
Neoplasms

Cite this

Sutcliffe, Elissa ; Li, Jasmine ; Zafar, Anjum ; Hardy, Kristine ; Ghildyal, Reena ; Norris, Nicole ; Lim, Chloe (Pek Siew) ; Milburn, Peter ; Casarotto, Marco ; Denyer, Gareth ; Rao, Sudha. / Chromatinized Protein Kinase C-theta: Can It Escape the Clutches of NF-kB?. In: Frontiers in Immunology. 2012 ; Vol. 3, No. E. pp. 260-273.
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Sutcliffe, E, Li, J, Zafar, A, Hardy, K, Ghildyal, R, Norris, N, Lim, CPS, Milburn, P, Casarotto, M, Denyer, G & Rao, S 2012, 'Chromatinized Protein Kinase C-theta: Can It Escape the Clutches of NF-kB?', Frontiers in Immunology, vol. 3, no. E, pp. 260-273. https://doi.org/10.3389/fimmu.2012.00260

Chromatinized Protein Kinase C-theta: Can It Escape the Clutches of NF-kB? / Sutcliffe, Elissa; Li, Jasmine; Zafar, Anjum; Hardy, Kristine; Ghildyal, Reena; Norris, Nicole; Lim, Chloe (Pek Siew); Milburn, Peter; Casarotto, Marco; Denyer, Gareth; Rao, Sudha.

In: Frontiers in Immunology, Vol. 3, No. E, 2012, p. 260-273.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chromatinized Protein Kinase C-theta: Can It Escape the Clutches of NF-kB?

AU - Sutcliffe, Elissa

AU - Li, Jasmine

AU - Zafar, Anjum

AU - Hardy, Kristine

AU - Ghildyal, Reena

AU - Norris, Nicole

AU - Lim, Chloe (Pek Siew)

AU - Milburn, Peter

AU - Casarotto, Marco

AU - Denyer, Gareth

AU - Rao, Sudha

PY - 2012

Y1 - 2012

N2 - We recently provided the first description of a nuclear mechanism used by Protein Kinase C-theta (PKC-θ) to mediate T cell gene expression. In this mode, PKC-θ tethers to chromatin to form an active nuclear complex by interacting with proteins including RNA polymerase II, the histone kinase MSK-1, the demethylase LSD1, and the adaptor molecule 14-3-3ζ at regulatory regions of inducible immune response genes. Moreover, our genome-wide analysis identified many novel PKC-θ target genes and microRNAs implicated in T cell development, differentiation, apoptosis, and proliferation. We have expanded our ChIP-on-chip analysis and have now identified a transcription factor motif containing NF-κB binding sites that may facilitate recruitment of PKC-θ to chromatin at coding genes. Furthermore, NF-κB association with chromatin appears to be a prerequisite for the assembly of the PKC-θ active complex. In contrast, a distinct NF-κB-containing module appears to operate at PKC-θ targeted microRNA genes, and here NF-κB negatively regulates microRNA gene transcription. Our efforts are also focusing on distinguishing between the nuclear and cytoplasmic functions of PKCs to ascertain how these kinases may synergize their roles as both cytoplasmic signaling proteins and their functions on the chromatin template, together enabling rapid induction of eukaryotic genes. We have identified an alternative sequence within PKC-θ that appears to be important for nuclear translocation of this kinase. Understanding the molecular mechanisms used by signal transduction kinases to elicit specific and distinct transcriptional programs in T cells will enable scientists to refine current therapeutic strategies for autoimmune diseases and cancer.

AB - We recently provided the first description of a nuclear mechanism used by Protein Kinase C-theta (PKC-θ) to mediate T cell gene expression. In this mode, PKC-θ tethers to chromatin to form an active nuclear complex by interacting with proteins including RNA polymerase II, the histone kinase MSK-1, the demethylase LSD1, and the adaptor molecule 14-3-3ζ at regulatory regions of inducible immune response genes. Moreover, our genome-wide analysis identified many novel PKC-θ target genes and microRNAs implicated in T cell development, differentiation, apoptosis, and proliferation. We have expanded our ChIP-on-chip analysis and have now identified a transcription factor motif containing NF-κB binding sites that may facilitate recruitment of PKC-θ to chromatin at coding genes. Furthermore, NF-κB association with chromatin appears to be a prerequisite for the assembly of the PKC-θ active complex. In contrast, a distinct NF-κB-containing module appears to operate at PKC-θ targeted microRNA genes, and here NF-κB negatively regulates microRNA gene transcription. Our efforts are also focusing on distinguishing between the nuclear and cytoplasmic functions of PKCs to ascertain how these kinases may synergize their roles as both cytoplasmic signaling proteins and their functions on the chromatin template, together enabling rapid induction of eukaryotic genes. We have identified an alternative sequence within PKC-θ that appears to be important for nuclear translocation of this kinase. Understanding the molecular mechanisms used by signal transduction kinases to elicit specific and distinct transcriptional programs in T cells will enable scientists to refine current therapeutic strategies for autoimmune diseases and cancer.

U2 - 10.3389/fimmu.2012.00260

DO - 10.3389/fimmu.2012.00260

M3 - Article

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SP - 260

EP - 273

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - E

ER -