Abstract
Recently there has been much interest in the Regulators of Calcineurin (RCAN) proteins which are important endogenous modulators of the calcineurin-NFATc signalling pathway. They have been shown to have a crucial role in cellular programmes such as the immune response, muscle fibre remodelling and memory, but also in pathological processes such as cardiac hypertrophy and neurodegenerative diseases. In vertebrates, the RCAN family form a functional subfamily of three members RCAN1, RCAN2 and RCAN3 whereas only one RCAN is present in the rest of Eukarya. In addition, RCAN genes have been shown to collocate with RUNX and CLIC genes in ACD clusters (ACD21, ACD6 and ACD1). How the RCAN genes and their clustering in ACDs evolved is still unknown. After analysing RCAN gene family evolution using bioinformatic tools, we propose that the three RCAN vertebrate genes within the ACD clusters, which evolved from single copy genes present in invertebrates and lower eukaryotes, are the result of two rounds of whole genome duplication, followed by a segmental duplication. This evolutionary scenario involves the loss or gain of some RCAN genes during evolution. In addition, we have analysed RCAN gene structure and identified the existence of several characteristic features that can be involved in RCAN evolution and gene expression regulation. These included: several transposable elements, CpG islands in the 5′ region of the genes, the existence of antisense transcripts (NAT) associated with the three human genes, and considerable evidence for bidirectional promoters that regulate RCAN gene expression. Furthermore, we show that the CpG island associated with the RCAN3 gene promoter is unmethylated and transcriptionally active. All these results provide timely new insights into the molecular mechanisms underlying RCAN function and a more in depth knowledge of this gene family whose members are obvious candidates for the development of future therapies.
Highlights
The Regulators of Calcineurin proteins (RCAN, formerly known as DSCR and calcipressin, amongst other terms) are important regulators of several cellular programmes [1]
Overall Evolution of RCAN Genes We have previously reported that the RCAN family consists of three genes that constitute a functional subfamily in gnathostomes, with the exception of some fishes (Tetraodon nigroviridis and Takifugu rubripens), while only one RCAN gene is found in the rest of the Eukarya [16]
We look in depth at the evolution of the RCAN gene family in jawed vertebrates, their human gene structure and regulatory elements involved in human RCAN gene expression in order to improve our knowledge of this gene family
Summary
The Regulators of Calcineurin proteins (RCAN, formerly known as DSCR and calcipressin, amongst other terms) are important regulators of several cellular programmes [1]. RCANs have been mainly described to act through physical binding and modulation of the Ca2+ and calmodulin-dependent serine-threonine phosphatase calcineurin (Cn; known as PPP3, formerly PP2B) [1,7,8,9]. This enzyme has many important physiological substrates including the transcription factors cytosolic Nuclear Factors of Activated T cells (NFATc) [10]. It is worth noting that Cn is present in all the Eukarya and that the NFATc proteins are restricted to vertebrates (reviewed in [10])
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