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c-Maf

Short Introduction of c-Maf

c-Maf is a member of the basic leucine zipper transcription factors belonging to the AP-1 family. It has been shown that c-Maf is overexpressed in multiple myeloma (MM), enhancing tumor-stroma interactions. In the monocyte/macrophage lineage, c-Maf is essential for macrophage self-renewal.

Structures of the human Maf family proteins and the c-Jun bZIP transcription factor. Fig.1 Structures of the human Maf family proteins and the c-Jun bZIP transcription factor. (Imbratta, 2020)

c-Maf and γδ T Cell

Maf deficiency caused an absolute lineage block at the immature CD24+CD45RBlo γδ thymocyte stage. c-Maf enforced Tγδ17 cell identity by promoting chromatin accessibility and expression of key type 17 program genes, notably Rorc and Blk, while antagonizing the transcription factor TCF1, which promotes interferon-γ-producing γδ T cells (Tγδ1 cells). Furthermore, γδ T cell antigen receptor (γδ TCR) signal strength tuned c-Maf expression. c-Maf is considered a universal regulator of Tγδ17 cell differentiation and maintenance.

c-Maf in T Cells

c-Maf expression and activity are regulated at transcriptional, post-transcriptional, as well as post-translational levels. Transcription factors and RNA-mediated silencing control the amount of Maf transcripts, while phosphorylation will modify the activity, subcellular localization, and half-life of the protein.

In T cells, antigenic stimuli that modulate the stability of the c-Maf encoding mRNAs and/or the c-Maf protein may also induce the expression of transcriptional activators, or may cooperate with independent transcriptional stimuli, such as cytokine-driven STAT factors to induce c-Maf transcription. The selective use of those pathways by different stimuli and in distinct cell populations provides the potential for tailoring c-Maf expression to different circumstances.

Role of c-Maf in Tumor-Infiltrating CD8 T Cells

c-Maf is not expressed in CD8 T cells at a steady state. The expression of c-Maf in CD8 T cells was first described in tumor-infiltrating lymphocytes (TILs) obtained from a mouse melanoma model and melanoma patient.

Overexpression of c-Maf in CD8 T cells leads to a strong repression of IFN-γ and IL-2 production, and an increased expression of genes associated with T cell exhaustion. A dysfunctional state of T cells observed during chronic infections or in tumor-infiltrating lymphocytes (TILs).

When c-Maf was knocked-out in tumor-specific CD8 T cells, those cells had a much higher capacity to restrain tumor growth through increased IFN-γ production and increased survival.

c-Maf and Disease

The combined upregulation of multiple type 2 cytokines by c-Maf transgenic T-cells correlates with disease attenuation in some, but not all, models of diabetes. In the model of spontaneous diabetes, c-Maf significantly inhibits disease. Because diabetes in this model is dependent on major histocompatibility complex (MHC) class II restricted CD4 T-cell effector function, disease inhibition is most likely a consequence of the c-Maf-mediated early shift in type 2 cytokines produced by antigen-specific CD4 cells. c-Maf had no significant direct effects on T-cell proliferation in vitro or peri-insulitis in vivo.

c-Maf and Cancer

  • c-Maf is also highly expressed in over half of the angioimmunoblastic T-cell lymphomas (AITL). Transgenic overexpression of c-Maf in T cells regulates the same gene expression set as in plasma cells and induces T-cell lymphoma development in mice, therefore indicating that c-Maf is a bona fide oncogene contributing to the progression of hematological malignancies.
  • c-Maf is also expressed by other cancers, such as renal or head and neck cancer. Its expression is not systematically correlated with a bad prognosis.
  • Overexpression of c-Maf is a much more frequent oncogenic event in MM. Scientists detected significant levels of c-Maf expression in 50% of myeloma cell lines and myeloma cells (MC) purified from patient bone marrow samples. c-Maf overexpression in MM drives cyclin D2, integrin β7, and ARK5 expression and leads to proliferation, adhesion to bone marrow stromal cells, invasion, and migration of plasma cells.

The oncoprotein c-Maf and its transactivation targets in multiple myeloma. Fig.2 The oncoprotein c-Maf and its transactivation targets in multiple myeloma. (Kienast, 2004)

Many proteins secreted by γδ T cells play an important role in immune regulation. To better understand and explore the role of these proteins, Creative Biolabs has a series of related services in terms of γδ T cell. If you have any questions, please contact us.

References

  1. Imbratta, C.;et al. c-MAF, a Swiss Army Knife for Tolerance in Lymphocytes. Frontiers in Immunology. 2020, 11.
  2. Kienast, J.; Berdel WE. c-Maf in multiple myeloma: an oncogene enhancing tumor-stroma interactions. Cancer Cell. 2004, 5(2): 109-110.
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