The RUNX genes

Cure Arthritis Naturally

Beat Arthritis Naturally

Get Instant Access

RUNX1 is one of the three human genes belonging to the family of highly conserved runt-domain-encoding genes [16]. These are RUNX1 located on human chromosome 21q22.3, RUNX2 mapped to chromosome 6p21 and RUNX3 lying on chromosome 1p36 [17-19]. All three regions have been linked to one or several autoimmune or rheumatic diseases [20]. RUNX proteins possess a striking feature to either repress or activate transcription of a large variety of genes depending on the co-factors present and architecture of the target sequence [21]. Another feature is a common binding site recognised by all RUNX proteins, a fact that hampers their functional analyses [22, 23].

The three RUNX genes show extensive structural similarities that include not only a highly conserved region encoding the runt domain, but also the presence of two promoters P1 (distal) and P2 (proximal) and a number of alternative splice iso-forms [24-29]. Besides, RUNX proteins function as heterodimers formed by interaction with the CBFp subunit [30], which, first, stabilises the Runx proteins by protecting them from rapid ubiquitin-mediated proteolysis [31] and, second, enhances their DNA-binding affinity by several fold [32, 33].

RUNX1 (also known as AML1, PEBP2aB or CBFA2) was primarily implicated in acute myeloid leukaemia. Chromosomal translocations involving AML1 gene (t8;21) were found in cells from 18% of patients with acute myeloid leukaemia (AML), (t12;21) accounting for approximately 25% of ALL paediatric cases, and the most rare rearrangements (t3;21) were associated with CML [34-36]. Although, the question of whether the fusion proteins themselves are the initial cause of the cancer, or it is the consequence of insufficiency of the normal RUNX1 gene function, or the combination of both, remains open. It was shown that gene dosage is very important for the function of all RUNX genes.

RUNX2 (AML3/PEBP2PA/CBFA1) has a major role in bone and cartilage formation by regulating several target genes expressed in these cells [37, 38]. Limb shortening due to disturbances in chondrocyte development, vascular invasion, osteoclast differentiation and periosteal bone formation were observed in a mouse model of dominant negative Runx2 [39]. Mutations in RUNX2 lead to a facial craniodysplasia syndrome in humans [40].

RUNX3 (AML2/PEBP2aC/CBFA3) is the shortest of the three genes. About half of the patients with gastric cancer show substantially decreased levels of Runx3 in epithelial cells from gastric mucosa [41]. Both hemizygous deletions and epigenetic silencing by hypermethylation of the promoter region were found to be involved in it [42]. RUNX3 appears to be also involved in chondrocyte proliferation and maturation [39].

Thus, in short, the RUNX proteins are expressed primarily in skeletal and hematopoietic tissues and cells. In skeletal tissues, their main sites of expression are osteoblasts and chondrocytes, while they are expressed differentially at various stages of hematopoietic development. RUNX1 has been shown to be a major regulator of haematopoiesis, as mice with dominant negative mutations die early of a lack of haematopoietic development [43]. Similarly, mice deficient for RUNX2 have important skeletal abnormalities. Mice deficient for RUNX3 show development of gastric cancer. However, more recent studies have shown an important role of the RUNX proteins in immune system development and inflammation.

There is a fine regulation of the RUNX genes that is not completely understood or even fully described. As these genes can be expressed concomitantly within the same cell but at different levels, precise transcriptional and translational control of such expression may be crucial for the regulation of target genes. A very elegant model has been recently proposed for the silencing of the CD4 locus during T-cell development towards CD8+ commitment [44, 45]. RUNX1 was shown to be an active transcriptional repressor of the CD4 gene in double negative (DN) immature thymocytes, while RUNX3 maintained silencing of CD4 in CD8+SP T-cells through epigenetic mechanisms, showing the context dependency of the regulatory effects of both proteins. RUNX2 was also found expressed in the thymus, but its role has not been established [46].

All three RUNX genes contain multiple recognition sites for themselves in the promoter regions, which makes autoregulation and/or cross-regulation possible. The two examples have been presented so far with RUNX2 autoregulated by negative feedback during osteoblast differentiation and skeletal development [47], and RUNX3 downregulating RUNX1 gene in human B-cells [48] by binding to its P1 promoter. Competition between RUNX proteins to exert its functions for association with CBFp might also contribute to the transcriptional control of target genes [49].

It is now accepted that the RUNX proteins are important in TGF-P signal transduction. TGF-P is a pleiotropic cytokine playing a fundamental role in cell growth and differentiation, and known to be one of the strongest immunosuppressor and anti-inflammatory cytokines. Many of the effects of TGF-P are mediated via the RUNX proteins [50-53]. This is supported by the demonstration of the physical interaction of the R-Smad transcription factors transmitting the signals from TGF-P receptors into the nucleus [54], and RUNXes, and by the finding of functional sites for RUNX2 in the TGF-P type I receptor promoter [51, 55]. TGF-P induces immunoglobulin class switch recombination in B lymphocytes towards IgA, and this is mediated by RUNX3 through direct interaction with its binding sites in the Ig Ca promoter. The Smads are also essential for IgA synthesis as disruption of sites for Smads and RUNX does impair IgA transcription [56], a further example of the mediation of TGF-P signalling through RUNXes [52, 55].

Recently, interesting data has been published as to the role of RUNX3 in inflammation. Using a KO mouse for RUNX3, Fainaru et al. have shown that these mice develop spontaneous eosinophilic lung inflammation and that this is dependent on the signalling through TGF-P [57]. Interestingly, wild type dendritic cells (WT DC) normally overexpress Runx3 upon activation and respond to TGF-P-mediated inhibition. While KO DC appeared to be insensitive to TGF-P-induced inhibition, accumulated in the alveoli and maintained increased expression of MHC II, OX40L, CD80 and CD86, and thus had the capacity to over-stimulate T lymphocytes, which drive inflammation by enhanced recruitment of eosinophils to the lungs. Furthermore, in the animals developing airway inflammation, there was an increase in TH2 cytokines. At 3 weeks of age, the RUNX3 KO mice also develop inflammatory bowel disease characterised by leukocyte infiltration, mucosal hyperplasia, lym-phoid cluster formation and increased production of IgA [58]. This supports the potential role of the RUNX proteins in inflammatory diseases.

What could the pathogenic role of the RUNX genes be in rheumatic diseases? There is still much to be done on this regard. Although, one could anticipate that RUNXes are the key transcription factors that may participate in the pathogenesis at two different levels: directly or indirectly. At the first level, their function could be influenced by altered production of diverse proinflammatory/anti-inflammatory stimuli or mediators and thus providing the basis for sustained pathogeneic changes in cell responses or development/maturation or even tissue damages, such as for TGF-P. It is known, for instance that TGF-P production is decreased in lupus nephritis; however it is uncertain if this effect is a cause or consequence of RUNX regulation. RUNX1 and RUNX3 could be involved in dendritic cell maturation and the subsequent the development of Th2 responses [59], while RUNX2 could be suspected to be involved as a promoter of joint damage, that is, increasing susceptibility to the development of bone erosions. As RUNX2 is needed for osteoblast and chondrocyte development, aberrant expression of this regulator may decrease the capacity of the bone to regenerate after damage incurred by the immune system.

Also, mutations of the RUNX genes, both in coding and regulatory regions, affecting their function or expression, may change transcriptional patterns of particular cell populations in such a way that could give rise to autoimmunity. It is thus of great interest to analyse if there is an increase in risk of developing of autoimmune diseases in patients with naturally occurring mutations of RUNX1 gene, such as AML patients with translocations of chromosome 21, individuals with Down syndrome [60, 61] or diseases described caused by monogenic mutations in the RUNX genes [62], such as familial mutations leading to haploinsufficiency and a familial platelet disorder [63]. To date, only one report has been made between genetic susceptibility of RUNX1 and rheumatoid arthritis in Japanese patients [64], however this report analysed only one polymorphism and has not been replicated in other populations. No genetic association with the other RUNX genes has been reported.

On another level, RUNXes may be involved in the pathogenesis of autoimmune rheumatic diseases indirectly through impaired binding to the target regions affected by regulatory mutations or polymorphisms in the target genes. The examples for the latter case are the PD1.3A polymorphism mentioned above and a SNP disrupting the binding site for RUNX1 in the organic cation transporter gene SLC22A4 involved in pathogenesis of RA [64] and the example of the loss of the RUNX binding site described to be involved in susceptibility for psoriasis [65] in a region between the genes SLC9A3R1 and NAT9, although no particular association has been found with psoriatic arthritis and the described polymorphisms.

Was this article helpful?

0 0
Treating Rheumatoid Arthritis With Herbs Spices Roots

Treating Rheumatoid Arthritis With Herbs Spices Roots

Did You Know That Herbs and Spices Have Been Used to Treat Rheumatoid Arthritis Successfully for Thousands of Years Do you suffer with rheumatoid arthritis Would you like to know which herbs and spices naturally reduce inflammation and pain 'Treating Rheumatoid Arthritis with Herbs, Spices and Roots' is a short report which shows you where to start.

Get My Free Ebook

Post a comment