%0 Journal Article
%T RASSF1A Signaling in the Heart: Novel Functions beyond Tumor Suppression
%A Dominic P. Del Re
%A Junichi Sadoshima
%J Molecular Biology International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/154283
%X The RASSF proteins are a family of polypeptides, each containing a conserved Ras association domain, suggesting that these scaffold proteins may be effectors of activated Ras or Ras-related small GTPases. RASSF proteins are characterized by their ability to inhibit cell growth and proliferation while promoting cell death. RASSF1 isoform A is an established tumor suppressor and is frequently silenced in a variety of tumors and human cancer cell lines. However, our understanding of its function in terminally differentiated cell types, such as cardiac myocytes, is relatively nascent. Herein, we review the role of RASSF1A in cardiac physiology and disease and highlight signaling pathways that mediate its function. 1. Introduction The Ras association domain family (RASSF) consists of 10 members: RASSF1-10. Additionally, splice variants of RASSF1, 5 and 6 have been identified [1]. Importantly, all isoforms contain a Ras association (RA) domain either in their C-terminal (RASSF1-6) or N-terminal (RASSF7-10) regions [2]. To date, no known catalytic activity has been described for this family, and the general consensus supposes that RASSF proteins function as scaffolds to localize signaling in the cell. Accordingly, protein-protein interactions are critical in mediating their biological functions. RASSF1 isoform A (RASSF1A) is the most characterized member of the RASSF family. This paper will focus primarily on RASSF1A and its role in cardiovascular biology. 2. RASSF1A RASSF1A was first identified and described by Dammann et al. in 2000 [3]. The RASSF1 gene encodes multiple splice variants, including the two predominant isoforms, RASSF1A and C. The RASSF1A isoform is the longest variant of the RASSF1 gene. Structurally, RASSF1A is a product of exons 1¦Á, 2¦Á/¦Â, 3, 4, 5, and 6, while RASSF1C consists of exons 2¦Ã, 3, 4, 5, and 6. Both isoforms contain a C-terminal RA domain; however, RASSF1A has an additional C1 domain that is not present in RASSF1C. The RASSF1 gene is located on Chr3p21.3 [3]. This short arm of chromosome 3 is known to exhibit loss of heterozygosity in many tumor models and is thought to harbor tumor suppressor genes. As the literature has shown, RASSF1A fits this description. The RASSF1A promoter contains a CpG island that shows a high frequency of hypermethylation in tumors, thereby silencing RASSF1A expression in many human cancers including lung, breast, ovarian, renal, and bladder [4¨C7]. RASSF1A expression is also lost in numerous cancer cell lines, while RASSF1C expression is seemingly unaffected [4]. Interestingly, recent work suggests that
%U http://www.hindawi.com/journals/mbi/2012/154283/