Abstract
All living organisms exhibit autonomous daily physiological and behavioural rhythms to help them synchronize with the environment. Entrainment of circadian rhythm is achieved via activation of cyclic AMP (cAMP) and mitogen-activated protein kinase signaling pathways. NonO (p54nrb) is a multifunctional protein involved in transcriptional activation of the cAMP pathway and is involved in circadian rhythm control. Rasd1 is a monomeric G protein implicated to play a pivotal role in potentiating both photic and nonphotic responses of the circadian rhythm. In this study, we have identified and validated NonO as an interacting partner of Rasd1 via affinity pulldown, co-immunoprecipitation and indirect immunofluorescence studies. The GTP-hydrolysis activity of Rasd1 is required for the functional interaction. Functional interaction of Rasd1-NonO in the cAMP pathway was investigated via reporter gene assays, chromatin immunoprecipitation and gene knockdown. We showed that Rasd1 and NonO interact at the CRE-site of specific target genes. These findings reveal a novel mechanism by which the coregulator activity of NonO can be modulated.
Highlights
The cyclic AMP (cAMP)-dependent pathway is known to respond to information obtained from numerous extracellular stimuli to regulate processes including synaptic plasticity, neuronal differentiation, circadian rhythm, memory, and glucose homeostasis [1,2,3,4,5,6]
We studied the roles of Rasd1 and NonO in the cAMP pathway
Our findings show that co-localisation of Rasd1 and NonO in the nucleus is associated with the repression of a subset of CREB target genes
Summary
The cAMP-dependent pathway is known to respond to information obtained from numerous extracellular stimuli to regulate processes including synaptic plasticity, neuronal differentiation, circadian rhythm, memory, and glucose homeostasis [1,2,3,4,5,6]. Specificity of the signal and the pathway induced is crucial to ensure that specific proteins are transcribed to perform precise functions in a tissue- and/or temporal-specific manner. This specificity is achieved by the type of signals, how the signals are detected and relayed to specific signaling proteins responding to the stimuli, and the subsequent interactions with other proteins, and is dependent on cell type and contexts. Regulation of the pathway at the transcriptional level is achieved by various mechanisms including inhibition of core transcription factor activity, sequestration, and competition for limiting factor [7,8,9]
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