The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology
Abstract
:Simple Summary
Abstract
1. Introduction
2. AP-1 in Plasma Cell Biology
2.1. Fra-1
2.2. Fra-2
2.3. B-ATF
3. AP-1 in Multiple Myeloma
3.1. c-Maf and MafB
3.2. c-Jun
3.3. JunB
3.4. AP-1 in Bone Metabolism and MM Bone Disease
4. Targeting AP-1 TFs for MM Therapy
4.1. Targeting Protein-Protein Interaction
4.2. Targeting Protein-DNA Interaction
4.3. Epigenetic Inhibitors
4.4. TF Degradation
4.5. Natural Products
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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AP-1 Member | Activity | Mechanism | References |
---|---|---|---|
Plasma cell biology | |||
Fra-1 | Suppresses B cell differentiation into PCs and decreases Ig production | Inhibition of Prdm1/Blimp-1 expression by preventing binding of c-Fos to the promoter | [27,28,29] |
Fra-2 | Enhances B cell proliferation and differentiation at multiple stages | Transcriptional induction of FOXO-1 and IRF-4 expression, and their downstream targets Ikaros, IL7Ra, Rag1/2 and Aiolos | [24] |
B-ATF | Essential for GC formation and effective CSR | Downstream of FOXO-1, modulating the expression of Aicda/AID and GLTs from the Ig locus of B cells in the GC | [30,31] |
Regulates B cell activation and GC response | Binding of B-ATF containing AP-1 complexes and IRF-4 to the AICE motif of target genes | [32,33] | |
Multiple myeloma | |||
c-Maf MafB | Overexpressed in MM | Chromosomal translocation t(14;16), t(14;20) MMSET/MEK/ERK/AP-1 signaling sequelae | [11,18,34] |
Promote MM cell proliferation, migration and invasion, survival, adhesion and pathological interactions with BMSC | Regulation of cyclin D2, ARK5, DEPTOR, and integrin β7 expression | [35,36,37] | |
Confer resistance to PIs bortezomib and carfilzomib | Abrogation of GSK3β-mediated proteasomal degradation of c-Maf and MafB | [38,39] | |
c-Jun | Lower expression in primary MM cells compared to normal PCs | Unknown | [40] |
Upregulated in MM cells by adaphostin or bortezomib Inhibits proliferation and induces apoptosis | Caspase-mediated c-Abl cleavage Upregulation of EGR-1 Upregulation of p53 | [41,42,43,44] | |
JunB | BMSC- and IL-6- triggered upregulation in MM cells | MEK/MAPK- and NFκB- dependent | [45] |
Promotes MM cell proliferation | Cell cycle regulation | ||
Protects MM cells against dexamethasone- and bortezomib- induced cell death | Inhibition of apoptotic pathways | ||
Promotes MM BM angiogenesis | Transcriptional regulation of angiogenic factors VEGF, VEGFB and IGF1 | [46] | |
Bone metabolism | |||
c-Fos | Regulates OC differentiation (Block in OC differentiation in mice lacking c-Fos) | Induced by RANKL and M-CSF Transcriptional regulation of Fra-1 and NFATc1 | [47,48,49,50] |
Fra-1 | Regulates OB activity and bone matrix formation (Mice overexpressing Fra-1 develop osteosclerosis) | Regulation of bone matrix component production by OBs (osteocalcin, collagen1α2, and matrix Gla protein) | [51,52] |
Fra-2 | Regulates OB differentiation (Fra-2-overexpressing mice are osteosclerotic) | Transcriptional regulation of osteocalcin and collagen1α2 | [53] |
Controls OC survival and size (Increased size and numbers of OCs in Fra-2-deficient mice) | Transcriptional induction of LIF via Fra-2: c-Jun heterodimers Modulation of LIF/LIF-receptor/PHD2/HIF1α signaling sequelae | [54] | |
JunB | Regulates OB proliferation and differentiation (Mice lacking JunB are osteopenic) | Cyclin D1 and cyclin A expression, and collagen1α2, osteocalcin and bone sialoprotein production | [55] |
Regulates OC proliferation and differentiation | Dimerization partner of c-Fos (?) |
Strategies | Inhibitors | Targets | References |
---|---|---|---|
Inhibition of protein-protein interactions | Peptidic inhibitors of c-Maf dimerization | Leucine zipper motif of c-Maf | [70] |
Peptide antagonists of c-Jun dimerization | Leucine zipper motif of c-Jun | [71,72,73,74] | |
Peptide antagonists of c-Jun: c-Fos dimerization | Leucine zipper motif of c-Jun or c-Fos | [75,76] | |
Leucine zipper peptide (Superzipper) | Leucine zipper dimerization domains of both c-Jun and c-Fos | [77] | |
Inhibition of protein- DNA binding | T-5224 | bZIP domain of c-Fos/AP-1 -DNA complex | [78,79] |
MLN944 (XR5944) | TRE | [80] | |
SR11302 | TRE | [81,82] | |
Dominant negative peptide A-Fos | bZIP domain of c-Jun | [83] | |
Regulation of epigenetic events | Valproic acid (VPA) Vorinostat (SAHA) Trichostatin A (TSA) LBH589 | HDAC (Transcriptional suppression of c-Jun and Fra-1 expression) | [84] |
TC-E 5003 (TC-E) | PRMT (Suppression of c-Jun expression and nuclear translocation) | [85] | |
Natural products | Curcumin | Suppression of c-Fos and c-Jun expression and their binding to DNA | [86] |
Resveratrol | Suppression of c-Fos and c-Jun expression and AP-1 activity | [87] | |
Veratramine | TRE | [88] |
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Fan, F.; Podar, K. The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology. Cancers 2021, 13, 2326. https://doi.org/10.3390/cancers13102326
Fan F, Podar K. The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology. Cancers. 2021; 13(10):2326. https://doi.org/10.3390/cancers13102326
Chicago/Turabian StyleFan, Fengjuan, and Klaus Podar. 2021. "The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology" Cancers 13, no. 10: 2326. https://doi.org/10.3390/cancers13102326
APA StyleFan, F., & Podar, K. (2021). The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology. Cancers, 13(10), 2326. https://doi.org/10.3390/cancers13102326