Phosphorylation of class II transactivator regulates its interaction ability and transactivation function

Sisk, Tyler J.; Nickerson, Kevin M.; Kwok, Roland P.S.; Chang, Cheong Hee

doi:10.1093/intimm/dxg116

Cited by 39 publications

(31 citation statements)

References 40 publications

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“…Interestingly, the Neu RTK activates the mitogen activated kinase signaling cascade, which in turn can increase the transcriptional activity of CIITA. 39,40 Variable levels of expression of the transduced genes and/or the extinction of MHC class II on tumor cells might also explain some of the differences in results between these studies.…”

Section: Discussionmentioning

confidence: 97%

Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice

et al. 2006

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The HER-2/Neu oncogene has been implicated in human and mouse breast cancer. Indeed, transgenic MMTV-neu mice expressing this oncogene from the mammary tumor virus long terminal repeat develop spontaneous mammary tumors and die within 1 year of life. We have expressed the class II transactivator (CIITA) and/or the costimulatory molecule CD80 (B7.1) in a mammary carcinoma cell line (MCNeuA) derived from these mice. Class II transactivator directs the expression of MHC class II and the machinery for antigen processing and presentation by this pathway. When injected into MMTV-neu mice, tumor cells expressing CD80 or CD80 and CIITA, were rejected completely. In addition, following the rejection of dual expressing cells, 75% of the mice were protected against the development of subsequent spontaneous tumors. Cells expressing only CD80 or CIITA were not as effective as antitumor vaccines in preventing the development of spontaneous tumors. Thus, converting cancer cells into antigen presenting cells could represent an effective immunotherapy for breast cancer.

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Section: Discussionmentioning

confidence: 97%

Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice

et al. 2006

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“…To generate stable cell lines expressing WT or DN PKCδ, RAW264.7 cells were transfected with WT, DN PKCδ or the empty vector, and selected with G418. The 1.1 kb pIV-driven luciferase plasmid and MHC class II Eα driven luciferase reporter plasmid were described previously (Sisk et al, 2003;Yao et al, 2006). The IRF-1 promoter construct that contains the GAS and NF-κB site (0.7kb) was kindly provided by Dr. Richard Pine (Public Health Research Institute, New York, NY) (Pine, 1997).…”

Section: Plasmid and Transfectionsmentioning

confidence: 99%

“…Two days later, the cells were treated with human IFN-γ for 12hrs. Cell lysates were prepared to measure the luciferase activity as described (Sisk et al, 2003). Luciferase activity was normalized with CMV promoter driven β-galactosidase expression.…”

Section: Plasmid and Transfectionsmentioning

confidence: 99%

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Role of PKCδ in IFN-γ-inducible CIITA gene expression☆

Kwon

Yao

Walter

et al. 2007

Molecular Immunology

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The class II transactivator (CIITA) is a key regulatory factor for MHC class II expression. Here, we demonstrate that PKCδ plays an important role in regulating IFN-γ-inducible CIITA gene expression in macrophages. Inhibition of PKCδ by either a PKCδ inhibitor or a dominant negative (DN) mutant form of PKCδ led to down-regulation of CIITA expression. The decrease in CIITA expression by PKCδ inhibition was in part due to the reduced recruitment of serine 727-phosphorylated Stat1 and histone acetyltransferases to the CIITA promoter. As a result, IFN-γ induced histone acetylation at the CIITA promoter is also compromised. However, inhibition of PKCδ did not affect IRF-1 expression or IRF-1 binding to the CIITA promoter. Therefore, we report, for the first time, that PKCδ is an essential signaling molecule to achieve the maximal expression of CIITA in response to IFN-γ in macrophages. In addition, although IRF-1 is a key transcription factor to activate the IFN-γ inducible CIITA promoter, the effect of PKCδ on CIITA expression is mediated primarily by serine phosphorylation of Stat1.

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“…Although the CIITA gene is subject to both constitutive and inducible expression, the CIITA protein is also targeted by posttranslational modifications that alter its activity. Phosphorylation within the PST domain of CIITA by the kinases protein kinase A, protein kinase C, GSK3, CK1, and ERK1/2 selectively enhance or inhibit target gene expression (34)(35)(36)(37)(38)(39). Acetylation of CIITA by p300/CBP and pCAF increases its transactivation ability (40,41), whereas deacetylation by HDAC1 leads to its proteasomal degradation (42).…”

mentioning

confidence: 99%

Identification of a Nuclear Export Sequence in the MHC CIITA

Chiu

Gold

Fettig

et al. 2015

The Journal of Immunology

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Initiation of an immune response through expression of MHC class II and related genes is under the control of the CIITA. Normally found in both the cytoplasm and nucleus, CIITA is tightly controlled by a variety of posttranslational modifications as well as interactions with other nuclear and cytoplasmic factors, whereas disruption of this dual subcellular localization impairs CIITA functioning and expression of target genes. Although CIITA has well-defined domains necessary for its nuclear import, the region responsible for the translocation of CIITA from the nucleus has not been characterized. In this study, we identify a leucine-rich motif at residues 717–724 that bears strong homology to known nuclear export sequence (NES) domains. Mutation of this region renders CIITA insensitive to treatment with leptomycin B, an inhibitor of nuclear export, whereas fusion of this domain to a heterologous GFP is sufficient to induce its export to the cytoplasm or cause its retention in the nucleus following leptomycin B treatment. Point mutations of specific leucine residues within the NES disrupt the normal subcellular distribution of the full-length CIITA, impair its ability to interact with the nuclear export factor CRM1, and enhance CIITA-induced gene expression from an MHC class II gene promoter. IFN-γ stimulation of class II genes is further enhanced by inhibiting the nuclear export of endogenous CIITA. Collectively, these data demonstrate the first identification of a specific NES within CIITA and place it among the other protein domains that contribute to the posttranslational regulation of CIITA activity.

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Phosphorylation of class II transactivator regulates its interaction ability and transactivation function

Cited by 39 publications

References 40 publications

Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice

Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice

Role of PKCδ in IFN-γ-inducible CIITA gene expression☆

Identification of a Nuclear Export Sequence in the MHC CIITA

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