ReviewMechanisms of Ca2+-dependent transcription
Introduction
Control of gene expression by Ca2+ is a complex phenomenon regulated by cytosolic and/or nuclear mechanisms that decode the specificities of the calcium signal in terms of amplitude, duration, frequency and spatial properties 1., 2., 3., 4., 5., 6.. Ca2+ has been considered to be compartmentalized into distinct nuclear and cytosolic Ca2+ pools [7], but in fact Ca2+ ions simultaneously trigger specific mechanisms according to the characteristics of the calcium signal and the possibly spatially restricted localization of specific effectors and targets. But irrespective of the origin of the Ca2+ ions — entry through calcium channels, release from intracellular stores, or generation of Ca2+ transients in the nucleus, as recently reported for isolated nuclei from plant cells [8•] — a unified general first stage of Ca2+-regulated mechanisms can be postulated. That is, the detection of increased intracellular concentrations of Ca2+ ions by specific Ca2+ sensors, which, in turn and more or less directly, transduce the Ca2+ signal into changes in the transcription rate of specific genes. With the exception of protein kinase C (PKC), calcium sensors are EF-hand-containing proteins including calmodulin (CaM), the prototype calcium sensor molecule (reviewed in [9]), and several members of the recoverin subfamily of Ca2+-binding proteins [10••].
Work over the past two years has helped to delineate three general mechanisms that follow the recognition of changes in Ca2+ ion concentration by a calcium sensor. First, the activation of signaling cascades of phosphorylation and dephosphorylation that either modify the transactivating properties of transcription factors or affect the nucleosome structure, changing the accessibility of the RNA polymerase II to specific genes. Second, the induction of Ca2+-dependent protein–protein interactions between the calcium sensor and transcription factors, or, generally, proteins involved in transcription as parts of the enhanceosome. As a result of this interaction, binding to DNA or recruitment of certain cofactors is modified. Last, Ca2+-induced changes in the binding properties of the calcium sensor to specific sites in the DNA. In this review, we will discuss recent advances in our knowledge of these different Ca2+-dependent mechanisms.
Section snippets
Signaling cascades conveying the Ca2+ signal to the nucleosomes
Minute changes in free intracellular Ca2+ are quickly transformed into changes in the activity of several kinases including protein kinase A (PKA), PKC, mitogen-activated protein kinases (MAPKs) (extracellular signal regulated kinase [ERK] and p38), Ca2+/CaM-dependent protein kinase (CaMK) and CaMKK. How the phosphorylation by these kinases of the transcriptional activators cAMP responsive element (CRE)-binding protein (CREB) and Elk culminates in the transactivation of the immediate early gene
Ca2+-dependent protein–protein interactions that regulate gene expression
The prototypic calcium sensor CaM is a multifunctional protein that can interact in both a Ca2+-dependent and a Ca2+-independent manner with numerous substrates other than kinases and phosphatases [9]. Among these, two types of interactions are particularly important in the control of gene expression by nuclear Ca2+: the interaction with basic helix–loop–helix (bHLH) transcription factors [44], and the uncoupling of class II HDACs from transcriptional repressor complexes [45••].
Transcription
Multiple Ca2+-dependent mechanisms regulate MEF2-dependent transcription
MCM1/agamous/deficiens/SRF (MADS) box transcription factors of the MEF-2 family including MEF-2A to MED-2D are important determinants in muscle differentiation and T-cell activation as they have transcriptional control of specific target genes [51]. In addition, Greenberg and co-workers [52••] have recently found that MEF-2A and MEF-2C are highly expressed in postmitotic neurons of the cerebellum and the cerebral cortex, respectively, and that expression of MEF-2 is essential for the survival
Ca2+-dependent binding of the transcriptional repressor DREAM to DNA
DRE antagonist modulator (DREAM) is a Ca2+-binding protein of the recoverin subfamily that in the absence of Ca2+ binds to a specific site in the DNA—the downstream regulatory element (DRE) site [63]—and represses transcription [10••]. With our co-workers [10••] we found that a series of EFmutDREAMs, containing mutation of two residues in any of the functional EF-hands, did not affect the binding to the DRE sequence and the repressor function, but completely prevented dissociation and
Conclusions
The identification of Ca2+-signaling mechanisms within the nucleus and nuclear effectors responsive to the Ca2+ signal has in part mirrored previous knowledge about cytosolic pathways (see also Update). Interestingly, nuclear pathways of phosphoinositide signaling and nuclear functions for inositol phosphates, including profound effects on transcription, have also been disclosed recently by Odom et al. [68••]. Furthermore, work during the past two years has shown that many mechanisms are
Update
Recent work from Means and co-workers [69••] also find reduced stimulus-dependent CREB phosphorylation in the cerebellum of CaMKII-deficient mice, as well as severe reduction in the Purkinje cell population.
In addition to prodynorphin and c-fos, we have recently demonstrated that the apoptotic gene hrk is also regulated by DREAM. In this case, in a Ca2+-dependent, but also PI3-kinase-dependent manner [70•].
Finally, it has been suggested that the nuclear compartment contains all the proteins
Acknowledgements
We thank the people in our laboratory for discussions. The work is supported by grants from Ministeria Ciencia y Technologia, Communidad Autónoma de Madrid and Janssen-Cilag SA.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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