MEF-2 isoforms' (A-D) roles in development and tumorigenesis

Abstract

Myocyte enhancer factor (MEF)-2 plays a critical role in proliferation, differentiation, and development of various cell types in a tissue specific manner. Four isoforms of MEF-2 (A-D) differentially participate in controlling the cell fate during the developmental phases of cardiac, muscle, vascular, immune and skeletal systems. Through their associations with various cellular factors MEF-2 isoforms can trigger alterations in complex protein networks and modulate various stages of cellular differentiation, proliferation, survival and apoptosis. The role of the MEF-2 family of transcription factors in the development has been investigated in various cell types, and the evolving alterations in this family of transcription factors have resulted in a diverse and wide spectrum of disease phenotypes, ranging from cancer to infection. This review provides a comprehensive account on MEF-2 isoforms (A-D) from their respective localization, signaling, role in development and tumorigenesis as well as their association with histone deacetylases (HDACs), which can be exploited for therapeutic intervention.

Keywords: ATLL; HDACi; HDACs; HTLV-1; MEF-2.

Figure 1. Basal expression of MEF-2 isoforms in organ systems and tissues in RNA and protein

The expression of MEF-2 isoforms are illustrated in the various organ systems at the transcriptome level in TPM (transcripts for kilobase million) via RNA-seq expression and the protein expression from high to low levels which is obtained from the immune-cytochemistry quantification (https://www.proteinatlas.org/).

Figure 2. Calcium signaling affecting MEF-2 transcription at steady state versus the activated state in T cells

MEF-2 is constitutively bound with co-repressor complex, which comprises of CABIN-1, HDAC3 and Class II HDACs along with SMRT/NCOR in steady state. With the activation of stimulus, calcium stores from the ER are released into the cytoplasm via the IP3 receptor activation. The Ca2+ activates the calmodulin-calcineurin complex, which dephosphorylates the inactive NFAT in the cytoplasm into activated NFAT and translocates into the nucleus (this has been observed in depolarized neurons and skeletal myoblasts in specific isoforms of MEF-2). In T-lymphocytes, Calcium influx activates the CamK and PKA, which allows the transcription of NF-ĸB. PKA phosphorylates CREB and pCREB/P300 complex translocates to the nucleus and the co-repressor shuttles out of the nucleus and allows the activation of MEF-2, in the proliferation of T cells (shown in Jurkat T-cell line in-vitro).

Figure 3. Activation of MEF-2 by PI3K-AKT and MAPK signaling

MEF-2 is also activated by PI3K/AKT pathway which activates mTOR as a downstream target and also increases the transcription of MyoD and MEF-2 along with other transcription factors. The receptor tyrosine kinase (RTK) under specific stimulus activates various different transcription factors of AP-1 family like c-JUN and FOS and aids in the activation of MEF-2 via the MAPK family of MEK/ERK.