Interferon-related developmental regulator 1 is aprotein that in humans is encoded by theIFRD1gene.[5][6] The gene is expressed mostly inneutrophils, skeletal and cardiac muscle, the brain, and the pancreas.[5][6]The rat and the mouse homolog genes of interferon-related developmental regulator 1 gene (and their proteins) are also known with the name PC4[7] and Tis21, respectively. IFRD1 is member of a gene family that comprises a second gene, IFRD2, also known as SKmc15.[5][6]
IFRD1 has been identified as amodifier gene forcystic fibrosis lung disease. In humans, neutrophil effector function is dependent on the type of IRFD1 polymorphism present in the individual. Human and mouse data both indicate that IFRD1 has a sizable impact on cystic fibrosis pathogenesis by regulating neutrophil effector function.[8]
IFRD1(also known as PC4 or Tis7, see above) participates to the process of skeletal muscle cell differentiation. In fact, inhibition of IFRD1 function in C2C12 myoblasts, by antisense IFRD1 cDNA transfection or microinjection of anti-IFRD1 antibodies, prevents their morphological and biochemical differentiation by inhibiting the expression ofMyoD andmyogenin, key master genes of muscle development.[9] A role for IFRD1 in muscle differentiation has been observed also in vivo. Muscles from mice lacking IFRD1 display decreased protein and mRNA levels of MyoD, and myogenin, and after muscle crash damage in young mice there was a delay in regeneration.[10]
Recently it has been shown that upregulation of IFRD1 in vivo in injured muscle potentiates muscle regeneration by increasing the production of staminal muscle cells (satellite cells).[11] The underlying molecular mechanism lies in the ability of IFRD1 to cooperate with MyoD at inducing the transcriptional activity ofMEF2C. This relies on the ability of IFRD1 to bind selectively MEF2C, thus inhibiting its interaction with HDAC4.[11][12] Therefore, IFRD1 appears to act as a positive cofactor of MyoD.[11][12] More recently it has been shown that IFRD1 potentiates muscle regeneration by a second mechanism that potentiates MyoD, i.e., by repressing the transcriptional activity of NF-κB, which is known to inhibit MyoD mRNA accumulation. IFRD1 represses the activity ofNF-κBp65 by enhancing the HDAC-mediated deacetylation of the p65 subunit, by favoring the recruitment of HDAC3 to p65. In fact, IFRD1 forms trimolecular complexes with p65 and HDAC3.[11]
Thus, IFRD1 can induce muscle regeneration acting as a pivotal regulator of the MyoD pathway through multiple mechanisms. Given the dramatic decrease of myogenic cells occurring in muscle degenerative pathologies such as Duchenne dystrophy, the ability of IFRD1 to potentiate the regenerative process suggests that IFRD1 might be a therapeutic target.
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^abcBuanne P, Incerti B, Guardavaccaro D, Avvantaggiato V, Simeone A, Tirone F (Nov 1998). "Cloning of the human interferon-related developmental regulator (IFRD1) gene coding for the PC4 protein, a member of a novel family of developmentally regulated genes".Genomics.51 (2):233–42.doi:10.1006/geno.1998.5260.PMID9722946.
^Montagnoli A, Guardavaccaro D, Starace G, Tirone F (October 1996). "Overexpression of the nerve growth factor-inducible PC3 immediate early gene is associated with growth inhibition".Cell Growth Differ.7 (10):1327–36.PMID8891336.
Varnum BC, Lim RW, Herschman HR (1989). "Characterization of TIS7, a gene induced in Swiss 3T3 cells by the tumor promoter tetradecanoyl phorbol acetate".Oncogene.4 (10):1263–5.PMID2797820.
Guardavaccaro D, Ciotti MT, Schäfer BW, Montagnoli A, Tirone F (1995). "Inhibition of differentiation in myoblasts deprived of the interferon-related protein PC4".Cell Growth Differ.6 (2):159–69.PMID7756174.
Guardavaccaro D, Montagnoli A, Ciotti MT, Gatti A, Lotti L, Di Lazzaro C, Torrisi MR, Tirone F (1994). "Nerve growth factor regulates the subcellular localization of the nerve growth factor-inducible protein PC4 in PC12 cells".J. Neurosci. Res.37 (5):660–74.doi:10.1002/jnr.490370514.PMID8028043.S2CID20845428.
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides".Gene.138 (1–2):171–4.doi:10.1016/0378-1119(94)90802-8.PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library".Gene.200 (1–2):149–56.doi:10.1016/S0378-1119(97)00411-3.PMID9373149.
Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K (2002). "Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants".Mol. Vis.8:205–20.PMID12107410.
Roth A, Gill R, Certa U (2003). "Temporal and spatial gene expression patterns after experimental stroke in a rat model and characterization of PC4, a potential regulator of transcription".Mol. Cell. Neurosci.22 (3):353–64.doi:10.1016/S1044-7431(02)00039-8.PMID12691737.S2CID2364009.
Imabayashi H, Mori T, Gojo S, Kiyono T, Sugiyama T, Irie R, Isogai T, Hata J, Toyama Y, Umezawa A (2003). "Redifferentiation of dedifferentiated chondrocytes and chondrogenesis of human bone marrow stromal cells via chondrosphere formation with expression profiling by large-scale cDNA analysis".Exp. Cell Res.288 (1):35–50.doi:10.1016/S0014-4827(03)00130-7.PMID12878157.
Guo H, Gao C, Mi Z, Zhang J, Kuo PC (2007). "Characterization of the PC4 binding domain and its interactions with HNF4alpha".J. Biochem.141 (5):635–40.doi:10.1093/jb/mvm066.PMID17317687.
