IFRD1

Interferon-related developmental regulator 1 is a protein that in humans is encoded by the IFRD1 gene.[5][6] The gene is expressed mostly in neutrophils, skeletal and cardiac muscle, brain, 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
Identifiers
Aliases	IFRD1, PC4, TIS7, interferon related developmental regulator 1
External IDs	OMIM: 603502 MGI: 1316717 HomoloGene: 31043 GeneCards: IFRD1
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q31.1 Start 112,422,968 bp[1] End 112,481,017 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12 B1|12 18.06 cM Start 40,201,567 bp[2] End 40,248,504 bp[2]
RNA expression pattern More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3475	15982
Ensembl	ENSG00000006652	ENSMUSG00000001627
UniProt	O00458	P19182
RefSeq (mRNA)	NM_001007245 NM_001197079 NM_001197080 NM_001550	NM_013562
RefSeq (protein)	NP_001007246 NP_001184008 NP_001184009 NP_001541	NP_038590
Location (UCSC)	Chr 7: 112.42 – 112.48 Mb	Chr 12: 40.2 – 40.25 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Clinical significance

IFRD1 has been identified as a modifier gene for cystic 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]

Inducer of muscle regeneration

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 of MyoD and myogenin, 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 of MEF2C. 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 of NF-κB p65 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.

Interactions

IFRD1 has been shown to interact with several proteins in the SIN3 complex including SIN3B, SAP30, NCOR1, and HDAC1.[13] Moreover, IFRD1 protein binds MyoD, MEF2C, HDAC4, HDAC3 and the p65 subunit of NF-κB, forming trimolecular complexes with HDAC3 and p65 NF-κB proteins.[11][12] IFRD1 protein also forms homodimers.[12]

References

1. GRCh38: Ensembl release 89: ENSG00000006652 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001627 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Buanne 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. PMID 9722946.
6. "Entrez Gene: IFRD1 interferon-related developmental regulator 1".
7. Tirone F, Shooter EM (March 1989). "Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene". Proc. Natl. Acad. Sci. U.S.A. 86 (6): 2088–92. Bibcode:1989PNAS...86.2088T. doi:10.1073/pnas.86.6.2088. PMC 286853. PMID 2467301.
8. Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL (April 2009). "Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease". Nature. 458 (7241): 1039–42. Bibcode:2009Natur.458.1039G. doi:10.1038/nature07811. PMC 2841516. PMID 19242412.
9. 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. PMID 8891336.
10. Vadivelu SK, Kurzbauer R, Dieplinger B, Zweyer M, Schafer R, Wernig A, Vietor I, Huber LA (April 2004). "Muscle regeneration and myogenic differentiation defects in mice lacking TIS7". Mol. Cell. Biol. 24 (8): 3514–25. doi:10.1128/mcb.24.8.3514-3525.2004. PMC 381666. PMID 15060170.
11. Micheli L, Leonardi L, Conti F, Maresca G, Colazingari S, Mattei E, Lira SA, Farioli-Vecchioli S, Caruso M, Tirone F (February 2011). "PC4/Tis7/IFRD1 stimulates skeletal muscle regeneration and is involved in myoblast differentiation as a regulator of MyoD and NF-kappaB". J. Biol. Chem. 286 (7): 5691–707. doi:10.1074/jbc.M110.162842. PMC 3037682. PMID 21127072.
12. Micheli L, Leonardi L, Conti F, Buanne P, Canu N, Caruso M, Tirone F (March 2005). "PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C". Mol. Cell. Biol. 25 (6): 2242–59. doi:10.1128/MCB.25.6.2242-2259.2005. PMC 1061592. PMID 15743821.
13. Vietor I, Vadivelu SK, Wick N, Hoffman R, Cotten M, Seiser C, Fialka I, Wunderlich W, Haase A, Korinkova G, Brosch G, Huber LA (September 2002). "TIS7 interacts with the mammalian SIN3 histone deacetylase complex in epithelial cells". EMBO J. 21 (17): 4621–31. doi:10.1093/emboj/cdf461. PMC 125408. PMID 12198164.

Further reading

• Tirone F, Shooter EM (1989). "Early gene regulation by nerve growth factor in PC12 cells: induction of an interferon-related gene". Proc. Natl. Acad. Sci. U.S.A. 86 (6): 2088–92. Bibcode:1989PNAS...86.2088T. doi:10.1073/pnas.86.6.2088. PMC 286853. PMID 2467301.
• 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. PMID 2797820.
• 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. PMID 7756174.
• 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. PMID 8028043.
• 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. PMID 8125298.
• Bonaldo MF, Lennon G, Soares MB (1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• 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. PMID 9373149.
• Ge H, Si Y, Roeder RG (1998). "Isolation of cDNAs encoding novel transcription coactivators p52 and p75 reveals an alternate regulatory mechanism of transcriptional activation". EMBO J. 17 (22): 6723–9. doi:10.1093/emboj/17.22.6723. PMC 1171017. PMID 9822615.
• 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. PMID 12107410.
• Vietor I, Vadivelu SK, Wick N, Hoffman R, Cotten M, Seiser C, Fialka I, Wunderlich W, Haase A, Korinkova G, Brosch G, Huber LA (2002). "TIS7 interacts with the mammalian SIN3 histone deacetylase complex in epithelial cells". EMBO J. 21 (17): 4621–31. doi:10.1093/emboj/cdf461. PMC 125408. PMID 12198164.
• 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. PMID 12691737.
• 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. PMID 12878157.
• Micheli L, Leonardi L, Conti F, Buanne P, Canu N, Caruso M, Tirone F (2005). "PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C". Mol. Cell. Biol. 25 (6): 2242–59. doi:10.1128/MCB.25.6.2242-2259.2005. PMC 1061592. PMID 15743821.
• Vietor I, Kurzbauer R, Brosch G, Huber LA (2005). "TIS7 regulation of the beta-catenin/Tcf-4 target gene osteopontin (OPN) is histone deacetylase-dependent". J. Biol. Chem. 280 (48): 39795–801. doi:10.1074/jbc.M509836200. PMID 16204248.
• 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. PMID 17317687.