Heart Wall - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 280

Cardiac and endothelial cell lineages arise from a common progenitor. Synthesis
of transcription factor E-twenty six (ETS)-related protein ETSRP71 is transiently
induced in the endocardium and endothelium of the embryo by NKx2-5 that binds
to the NKX2-5 response element of the Etsrp71 gene promoter [ 507 ]. This factor
targets TIE2 receptor to specify cell fate in the developing heart.
Transcription factors, such as NKx2-5, DNA sequence GATA-binding protein
GATA4, and myocyte-specific enhancer factor-2C (MEF2c), are required for normal
cardiogenesis that is regulated by signaling molecules (e.g., bone morphogenetic
proteins, fibroblast growth factors, and Wnts). These signals induce or prevent the
early stage of cardiomyocyte differentiation.
In vertebrates, 3 members of the GATA family of zinc finger transcription factors
(GATA4-GATA6) operate in the heart in addition to products of the NK family of
homeobox genes [ 483 ]. Serum response factor, a member of the MADS box family,
mediates the transcription launched by various extracellular stimuli. Serum response
factor is inhibited by a homeodomain-only protein HOP that is unable to bind to
DNA, the synthesis of which is regulated by NKx2-5. Myocardin of the family
of SAP domain-containing nuclear proteins activates promoters of cardiomyocyte
genes via its association with serum response factor.
High-mobility group, nuclear protein HMGA2 12 regulates cardiomyocyte
differentiation, as it associates with BMP-responsive transcription factors SMAD1
and SMAD4 to synergistically activate the promoter of the cardiac NKX2-5
gene [ 508 ].
Transcription factors nuclear factor of activated T-cells NFAT3 and NFAT4 are
required for normal enzymatic activity of complex-2 and -4 of the respiratory chain
and mitochondrial oxidative activity [ 509 ].
Transcription factor E2F4 activates proliferation of developing cardiomyocytes
during cardiogenesis. 13 It operates as both a repressor and activator of cell pro-
liferation. It accumulates in the nucleus at the end of the S phase of the cell
division cycle, remains nuclear during mitosis, and disappears at the end of
cytokinesis [ 510 ]. Proliferation of cardiomyocytes ceases during the first weeks
12 The high-mobility group of non-histone chromatin proteins regulates the transcription of many
genes by chromatin remodeling and proteic complex formation on promoter and enhancer regions.
The HMG family of nuclear proteins includes 3 categories: HMGA, HMGB, and HMGN. Proteins
of the HMGA category are ubiquitous and abound during embryogenesis. The HMGA category
comprises 4 members: 3 splice variants (HMGA1a-HMGA1c) produced from the HMGA1 gene
transcript and HMGA2 encoded by HMGA2 gene.
13 The E2F family includes 9 members encoded by 8 genes (E2F1-E2F2, E2F3a-E2F3b, and
E2F4-E2F8). Three members are activators (E2F1-E2F3a), 6 are suppressors (E2F3b-E2F8).
In most quiescent cells, E2F4 is primarily nuclear. It localizes to the cytoplasm during entry into the
S phase. Nuclear E2F4 is mainly bound to Retinoblastoma-like protein-2 (or P130) in G0 phase and
Retinoblastoma protein and Retinoblastoma-like protein-1 (or P107) during the G1-S transition.