Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Widespread localization, responsiveness to numerous signal transduction systems, and broad substrate specificity enable the multifunctional CaM kinase to mediate regulation of many cellular functions. The abundance and diversity of CaM kinase substrates attest to its role as a multifunctional kinase. However, expanded identification of its in situ substrates as well as the consequences of their regulation by phosphorylation needs to be accomplished. Recently identified substrates have contributed to the list of potential functions for the CaM kinase. CREB is a hormonally stimulated transcriptional activator, and CaM kinase may lie on the pathway to its activation. This pathway could provide an interface between the potentiation of Ca2+ signals by CaM kinase and longer-term modifications of neuronal gene expression. The ryanodine receptor, as well as phospholamban, are involved in cardiac Ca2+ homeostasis, and their regulation by CaM kinase phosphorylation suggests the possibility of some feedback control of intracellular Ca2+ levels by CaM kinase. Regulation of neuronal plasticity by phosphorylation of synapsin I and of postsynaptic substrates necessary for long-term potentiation is another dynamic area of investigation. The study of substrates and their functions promises to continue providing exciting insights into the control of cellular signalling by Ca2+. Molecular cloning has enabled structural comparison of neuronal isoforms of the kinase, and has revealed the existence of closely related subunits. Subunits identified to data differ substantially only in two small variable domains, yet their expression in various tissues and during the course of development is precisely controlled. What unique properties do these small variable domains impart to the different isoforms? What directs high concentrations of kinase to a particular subcellular localization, and especially to the PSD? Further molecular cloning will undoubtedly determine whether other multifunctional CaM kinases with unique structures and properties exist. Finally, studies on the autoregulatory properties of CaM kinase have provided a fascinating picture of how this molecule can alone encode responses to Ca2+ signals, potentiating both the duration and magnitude of its activity. Autophosphorylation of the Thr286 autonomy site both traps calmodulin and permits Ca(2+)-independent activity after calmodulin dissociates. Further analysis of the role of the holoenzyme structure in these modulations will help clarify remaining mechanistic questions. Studies performed during the past few years have clearly established that this Ca(2+)-independent activity is generated in situ in response to a variety of cell stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Neuronal Ca2+/calmodulin-dependent protein kinases. 132 38

zif268/egr-1 is an immediate early response gene that is involved in regulation of growth and differentiation. Its mRNA encodes a sequence-specific transcriptional activator containing three zinc fingers that act as the DNA-binding domain. Although zif268/egr-1 is expressed in the nervous system during neuronal excitation, no target gene has yet been identified. Here we report that the zif268/egr-1 protein bound in vitro to two sites in the proximal regulatory region of the human synapsin I gene. The zif268/egr-1 protein was also shown to stimulate transcription from this control region in transactivation assays. Additionally, the presence of a putative neural-restrictive silencer element next to one of the zif268/egr-1-binding sites interfered with transactivation in a tissue-independent manner. An analysis of the temporal expression pattern of zif268/egr-1 and synapsin I during neuronal differentiation of P19 embryonal carcinoma cells revealed that zif268/egr-1 mRNA was induced on day 5 and synapsin I mRNA on day 8 after retinoic acid treatment. From this data we conclude that the synapsin I gene is a target of the zif268 transcription factor; however, intermediate factors may also be involved in the activation.
 ...
PMID:Regulation of synapsin I gene expression by the zinc finger transcription factor zif268/egr-1. 819 67

The development and function of the nervous system are directly dependent on a well defined pattern of gene expression. Indeed, perturbation of transcriptional activity or epigenetic modifications of chromatin can dramatically influence neuronal phenotypes. The phosphoprotein synapsin I (Syn I) plays a crucial role during axonogenesis and synaptogenesis as well as in synaptic transmission and plasticity of mature neurons. Abnormalities in SYN1 gene expression have been linked to important neuropsychiatric disorders, such as epilepsy and autism. SYN1 gene transcription is suppressed in non-neural tissues by the RE1-silencing transcription factor (REST); however, the molecular mechanisms that allow the constitutive expression of this genetic region in neurons have not been clarified yet. Herein we demonstrate that a conserved region of human and mouse SYN1 promoters contains cis-sites for the transcriptional activator Sp1 in close proximity to REST binding motifs. Through a series of functional assays, we demonstrate a physical interaction of Sp1 on the SYN1 promoter and show that REST directly inhibits Sp1-mediated transcription, resulting in SYN1 down-regulation. Upon differentiation of neuroblastoma Neuro2a cells, we observe a decrease in endogenous REST and a higher stability of Sp1 on target GC boxes, resulting in an increase of SYN1 transcription. Moreover, methylation of Sp1 cis-sites in the SYN1 promoter region could provide an additional level of transcriptional regulation. Our results introduce Sp1 as a fundamental activator of basal SYN1 gene expression, whose activity is modulated by the neural master regulator REST and CpG methylation.
 ...
PMID:Specificity protein 1 (Sp1)-dependent activation of the synapsin I gene (SYN1) is modulated by RE1-silencing transcription factor (REST) and 5'-cytosine-phosphoguanine (CpG) methylation. 2325 Jul 96