The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology

Abstract

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products.

ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma

“…The transcription of the EGFR/ERBB1 gene is positively regulated by several DNA binding proteins/transcription factors, including ETF [ 34 - 36 ], SP-1 [ 37 - 41 ], TCF [ 42 , 43 ], HOXB5 [ 44 , 45 ], RPF-1 [ 46 ] and AP-1 [ 33 , 47 - 49 ]. In an effort to gain insights into the mechanism of the observed transcript-level upregulation of the EGFR/ERB1 gene in MM samples, we set out to correlate the mRNA levels for EGFR/ERBB1 with the mRNA levels for DNA binding proteins/transcription factors capable of enhancing EGFR/ERBB1 expression.…”

“…We therefore examined if the ERBB1/EGFR expression in MM cells is correlated with expression levels of such DNA binding proteins. Our analyses provided unprecedented evidence that the amplified expression of EGFR/ERBB1 mRNA in MM cells was positively correlated with increased expression levels of mRNAs for several DNA binding proteins/transcription factors, including ETF [ 34 - 36 ], SP-1 [ 37 - 41 ], TCF [ 42 , 43 ], HOXB5 [ 44 , 45 ], RPF-1 [ 46 ] and AP-1 [ 33 , 47 - 49 ]. Based on these findings we propose a model according to which the mechanism of the observed transcript-level upregulation of the EGFR/ERB1 gene in MM samples is related to the upregulated expression of the correlated DNA binding proteins ( Figure 6 ).…”

Structural and Functional Properties of Activator Protein-1 in Cancer and Inflammation

“…Jun-Jun and Jun-Fos dimers preferentially bind to the phorbol 12-O-tetradecanoate-13-acetate (TPA)-responsive element (TRE; Consensus DNA sequence TGACTCA) [ 17 ]. AP-1 subunit members possess distinct dimerization capability [ 18 ], whereas c-Maf and Nrl can form heterodimers with c-Jun and c-Fos and Maf-related proteins, such as MafB, MafF, MafG, and MafK, form dimers only with Fos but not Jun. Certain dimers have a weak affinity for DNA sequences that deviate from the consensus AP-1 protein and can form unique DNA binding and TF activity interacting with other proteins outside [ 19 ].…”

Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma

“…Several reports were also conducted on the RAF-MEK1/2-ERK1/2 cascade and downstream c-Jun/Fos and Activator protein-1 (AP1) pathways, which regulate numerous systems. Epigenetic changes stimulate or inhibit AP-1 functions and give the possibility to aim at AP-1 transcriptomes [ 66 ] selectively. In addition to c-Maf and MafB, whose amounts are associated with a less important MBD, other AP-1 components have been correlated with lytic bone lesions in MM [ 67 , 68 ].…”