Dynamic Regulation of the Adenosine Kinase Gene during Early Postnatal Brain Development and Maturation

Abstract

The ubiquitous metabolic intermediary and nucleoside adenosine is a “master regulator” in all living systems. Under baseline conditions adenosine kinase (ADK) is the primary enzyme for the metabolic clearance of adenosine. By regulating the availability of adenosine, ADK is a critical upstream regulator of complex homeostatic and metabolic networks. Not surprisingly, ADK dysfunction is involved in several pathologies, including diabetes, epilepsy, and cancer. ADK protein exists in the two isoforms nuclear ADK-L, and cytoplasmic ADK-S, which are subject to dynamic expression changes during brain development and in response to brain injury; however, gene expression changes of the Adk gene as well as regulatory mechanisms that direct the cell-type and isoform specific expression of ADK have never been investigated. Here we analyzed potential gene regulatory mechanisms that may influence Adk expression including DNA promoter methylation, histone modifications and transcription factor binding. Our data suggest binding of transcription factor SP1 to the Adk promoter influences the regulation of Adk expression.

Adenosine Kinase, a Common Pathologic Biomarker for Human Pharmacoresistant Epilepsy

“…Interestingly, strong neuronal expression of ADK has been detected in human fetal brains (gestational week 13; temporal cortex) [26]. Dynamic changes in ADK gene transcription during early postnatal brain development was also documented, and binding of transcription factor specificity protein 1 to the ADK promoter influences the regulation of ADK expression [27].…”

“…Potential gene regulatory mechanisms including DNA promoter methylation, histone modifications and transcription factor binding may influence the dynamic regulation of the ADK gene during early postnatal brain development and maturation. Recent study indicated that binding of transcription factor specificity protein 1 to the ADK promoter influences the regulation of ADK expression [27].…”

“…Accordingly, the presence of BCs may indicate that the early stage of insults during the prenatal/in utero period leads to the dysfunction of the neural stem cells in the ventricular zone area, impair the normal function such as proliferation, maturation, migration, and terminal differentiation of neural stem cells [21]. At last, potential gene regulatory mechanisms may also influence the dynamic regulation of the ADK gene during early postnatal brain development and maturation [27].…”

Dysregulation of adenosine kinase isoforms in breast cancer

“…ADK has two isoforms: a long isoform, ADK-L, dominantly located in the nucleus [15]; and a short isoform, ADK-S, located in the cytoplasm [16]. The expression of ADK-L and ADK-S is dynamic during development with differentiated patterning; for example, ADK-L is dominantly expressed in early postnatal brain development, but then an ADK-S expression pattern becomes dominant in adult brain tissue [17]. This differential expression suggests a distinctive role for ADK-L (versus ADK-S) on proliferation and differentiation -two major nuclear activities that are tightly linked to cancer pathology [18].…”

Adenosine kinase and adenosine receptors A1R and A2AR in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP

“…This discrepancy may be explained by our antibody, which was selected for its optimal labeling in temporal lobe fixed‐tissue samples but has preferential recognition of the long isoform of ADK. ADK isoforms are developmentally regulated in the brain; the short isoform of ADK preferentially locates to the cytoplasm for adenosine clearance, whereas the long isoform is nuclear, with mainly epigenetic regulatory roles 35 …”