BMAL1 Regulates Glucokinase Expression Through E-Box Elements In Vitro

Paula Llanos, Patricio Ordenes, David B. Rhoads, Juan F. Santibanez, María García-Robles, Carola Millán

Producción científica: Capítulo del libro/informe/acta de congresoCapítulorevisión exhaustiva

Resumen

The organization of a circadian system includes an endogenous pacemaker system, input pathways for environmental synchronizing (entraining) stimuli, and output pathways through which the clock regulates physiological and behavioral processes, for example, the glucose-sensing mechanism in the liver. The liver is the central regulator of metabolism and one of our peripherals clocks. In mammals, central to this pacemaker are the transcription factors Circadian Locomotor Output Cycles Kaput (CLOCK) and BMAL1 (Brain and Muscle ARNT-Like 1). BMAL1 dimerizes with CLOCK, and this heterodimer then binds to the E-box promoter elements (CACGTG) present in clock and clock-controlled genes (CCGs). However, we are just beginning to understand how output pathways and regulatory mechanisms of CCGs are involved in rhythmic physiological processes. Glucokinase (GCK) is a fundamental enzyme in glucose homeostasis, catalyzing the high Km phosphorylation of glucose and allowing its storage. Moreover, gck is a dependent circadian gene. This study aims to determine the contribution of clock genes to hepatic gck expression and to define the specific role of E-box sequences on the circadian regulation of hepatic gck. Results showed that gck expression follows a circadian rhythm in rat hepatocytes in vitro. Accordingly, bmal1 expression induces the glucokinase circadian rhythmic expression in hepatocytes and the analysis of human and rat gck promoters, indicating the presence of E-box regions. Moreover, the basal activity of gck promoter was increased by clock/bmal1 co-transfection but inhibited by Period1/Period2 (per1/per2) co-transfection. Thus, the data suggest that the clock proteins tightly regulate the transcriptional activity of the gck promoter.

Idioma originalInglés
Título de la publicación alojadaAdvances in Experimental Medicine and Biology
EditorialSpringer
Páginas235-249
Número de páginas15
DOI
EstadoPublicada - 2023
Publicado de forma externa

Serie de la publicación

NombreAdvances in Experimental Medicine and Biology
Volumen1408
ISSN (versión impresa)0065-2598
ISSN (versión digital)2214-8019

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