HOP Signaling
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HOP Signaling

Cardiac myocyte proliferation and their differentiation early in development are dependent on the coordinate expression and action of SRF (Serum Response Factor), GATA4 (GATA Binding Protein-4) and the homeodomain factor NKX2.5 (NK2 Transcription Factor Related Locus-5). All three of these factors are expressed in developing cardiomyocytes and induce expression of cardiac genes. HOP (Homeodomain-Only Protein) physically interacts with SRF and inhibits activation of SRF-dependent transcription by inhibiting SRF binding to DNA. HOP gene encodes the smallest known homeodomain protein. HOP acts to modulate SRF-dependent transcription and cardiac-specific gene expression in the absence of intrinsic DNA binding capability (Ref.1). Although HOP is a homeodomain protein, it lacks a DNA-binding domain indicating that it does not regulate gene expression directly. SRF plays a dual role in cardiac development, influencing both cardiomyocyte proliferation and differentiation depending on the stage and other signals that are present. The sequestration of SRF by HOP blocks the activation of cardiac genes, preventing normal cardiac development. The influence of HOP on the opposing processes of cardiomyocyte differentation and proliferation reflect the interaction of HOP with SRF and the dual role that SRF plays. In early cardiac development, HOP opposes differentiation induction by SRF, while at later stages HOP opposes the proliferation induced by SRF (Ref.2).

The ability of HOP to repress transcriptional activity induced by NKX2.5 and Myocd (Myocardin) implicates a common mechanism of action involving SRF. Myocd functions by binding to SRF as does NKX2.5 and GATA4. Myocd belongs to the SAP domain family of nuclear proteins and activates cardiac muscle promoters by recruitment to SRF. NKX2.5 activates expression of HOP, which feeds back to inhibit the ability of NKX2.5 to activate SRF-dependent cardiac-specific genes such as NPPA (Natriuretic Peptide Precursor-A) and ACTC (Actin-Alpha Cardiac Muscle), while gene activation that is not dependent on SRF remains unaffected (Ref.2). SRF is a key regulator of immediate early gene expression, which frequently results in mitogenesis and also a key regulator of myogenic terminal differentiation. Many muscle-specific genes including skeletal, cardiac and smooth muscle Alpha-Actins contain combinations of at least three or more strong and weak affinity SREs (Serum Response Elements) that bind SRF in a highly cooperative manner. Collateral accessory factors then play essential roles in either facilitating or impeding SRF binding on multi-SRE muscle gene promoters, thus stimulating or repressing the transcription of SRF-dependent gene targets. The combination of NKX2.5 and GATA4 enhance the formation of SRF dependent DNA binding complexes. Conformational changes in SRF structure facilitated by NKX2.5 and GATA4 makes SRF a more efficient DNA binding factor; allowing it to bind to weaker non-consensus SREs and stimulating ACTC activity under limiting amounts of SRF. This indicates that NKX2.5 acts by providing a strong transcriptional activation domain, whereas the role of SRF is to attract NKX2.5 to the ACTC promoter and facilitate the recruitment of GATA4 (Ref.3). NKX2.5 and SRF strongly co-activate ACTC promoter. GATA4 induces a conformational change in NKX2.5 that displaces the C-terminal inhibitory domain, thus eliciting transcriptional activation of promoters containing NKX2.5 DNA binding targets. Therefore, ACTC promoter activity is regulated through the combinatorial interactions of at least three cardiac tissue-enriched transcription factors, NKX2.5, GATA4 and SRF (Ref.4).

HOP binds SRF, inhibits SRF-dependent gene expression and interferes with the cooperation of SRF with its co-activator Myocd. The dual role of HOP in cardiac growth control is reminiscent of the dichotomous roles of SRF in proliferation versus muscle differentiation and potentially contingent on differing signals and factors converging on SRF at different developmental stages or contexts. At a more fundamental level, several questions also remain to be addressed to understand better the roles of HOP in cardiac growth and development. If HOP is recruited to SRF, what are the signals or circumstances that promote HOPs recruitment? SRF is subject to both stimulatory and inhibitory binding partners, thereby forming either transcriptionally active or inactive assemblies. It is, of course, possible that HOP regulates factors beyond SRF alone (Ref.5). Mutations in the human HOP are with related cardiac complications. In the absence of HOP, the balance between proliferation and differentiation is disrupted with resulting excess or deficiency of cardiomyocytes, depending on other growth signals and factors (Ref.6).