IFRD1

Last updated
IFRD1
Identifiers
Aliases IFRD1 , PC4, TIS7, interferon related developmental regulator 1
External IDs OMIM: 603502 MGI: 1316717 HomoloGene: 31043 GeneCards: IFRD1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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: 40.25 – 40.3 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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, 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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">MyoD</span> Mammalian protein found in Homo sapiens

MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins known as myogenic regulatory factors (MRFs). These bHLH transcription factors act sequentially in myogenic differentiation. Vertebrate MRF family members include MyoD1, Myf5, myogenin, and MRF4 (Myf6). In non-vertebrate animals, a single MyoD protein is typically found.

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.

<span class="mw-page-title-main">Trichostatin A</span> Chemical compound

Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs. However, there are recent reports of the interactions of this molecule with Sirt 6 protein. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors that have a broad spectrum of epigenetic activities. Thus, TSA has some potential as an anti-cancer drug. One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer. Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span>

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

<span class="mw-page-title-main">Jun dimerization protein</span> Protein-coding gene in the species Homo sapiens

Jun dimerization protein 2 (JUNDM2) is a protein that in humans is encoded by the JDP2 gene. The Jun dimerization protein is a member of the AP-1 family of transcription factors.

<span class="mw-page-title-main">HDAC1</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases.

<span class="mw-page-title-main">Histone deacetylase 2</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the HDAC2 gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the core histones. As such, it plays an important role in gene expression by facilitating the formation of transcription repressor complexes and for this reason is often considered an important target for cancer therapy.

<span class="mw-page-title-main">HDAC3</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 3 is an enzyme encoded by the HDAC3 gene in both humans and mice.

<span class="mw-page-title-main">RBBP4</span> Protein-coding gene in the species Homo sapiens

Histone-binding protein RBBP4 is a protein that in humans is encoded by the RBBP4 gene.

<span class="mw-page-title-main">HDAC4</span>

Histone deacetylase 4, also known as HDAC4, is a protein that in humans is encoded by the HDAC4 gene.

<span class="mw-page-title-main">HDAC6</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene. HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorders.

<span class="mw-page-title-main">Myocyte-specific enhancer factor 2A</span> Protein-coding gene in the species Homo sapiens

Myocyte-specific enhancer factor 2A is a protein that in humans is encoded by the MEF2A gene. MEF2A is a transcription factor in the Mef2 family. In humans it is located on chromosome 15q26. Certain mutations in MEF2A cause an autosomal dominant form of coronary artery disease and myocardial infarction.

<span class="mw-page-title-main">Histone deacetylase 5</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 5 is an enzyme that in humans is encoded by the HDAC5 gene.

<span class="mw-page-title-main">BTG2</span> Protein-coding gene in the species Homo sapiens

Protein BTG2 also known as BTG family member 2 or NGF-inducible anti-proliferative protein PC3 or NGF-inducible protein TIS21, is a protein that in humans is encoded by the BTG2 gene and in other mammals by the homologous Btg2 gene. This protein controls cell cycle progression and proneural genes expression by acting as a transcription coregulator that enhances or inhibits the activity of transcription factors.

<span class="mw-page-title-main">HDAC9</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 9 is an enzyme that in humans is encoded by the HDAC9 gene.

<span class="mw-page-title-main">HDAC7</span>

Histone deacetylase 7 is an enzyme that in humans is encoded by the HDAC7 gene.

<span class="mw-page-title-main">HDAC8</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 8 is an enzyme that in humans is encoded by the HDAC8 gene.

<span class="mw-page-title-main">HDAC11</span> Protein-coding gene in the species Homo sapiens

Histone deacetylase 11 is a 39kDa histone deacetylase enzyme that in humans is encoded by the HDAC11 gene on chromosome 3 in humans and chromosome 6 in mice.

<span class="mw-page-title-main">BHLHE41</span> Protein-coding gene in the species Homo sapiens

"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000006652 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 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. 1 2 3 "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. 1 2 3 4 5 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. 1 2 3 4 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