IFRD1
Encyclopedia
Interferon-related developmental regulator 1 is a protein
that in humans is encoded by the IFRD1 gene
. The gene is expressed mostly in neutrophils, skeletal and cardiac muscle, brain, pancreas.
The rat and the mouse homolog genes of Interferon-related developmental regulator 1 gene (and their proteins) are also known with the name PC4 and Tis21, respectively.
IFRD1 is member of a gene family that comprises a second gene, IFRD2, also known as SKmc15.
lung disease.
and myogenin
, key master genes of muscle development. 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.
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). 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. Therefore, IFRD1 appears to act as a positive cofactor of MyoD. 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-kB, which is known to inhibit MyoD mRNA accumulation. IFRD1 represses the activity of NF-kB
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.
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.
with several proteins in the SIN3 complex including SIN3B
, SAP30
, NCOR1
, and HDAC1
. Moreover, IFRD1 protein binds MyoD
, MEF2C
, HDAC4
, HDAC3
and the p65 subunit of NF-kB
, forming trimolecular complexes with HDAC3
and p65 NF-kB
proteins. IFRD1 protein also forms homodimers.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the IFRD1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The gene is expressed mostly in neutrophils, skeletal and cardiac muscle, brain, pancreas.
The rat and the mouse homolog genes of Interferon-related developmental regulator 1 gene (and their proteins) are also known with the name PC4 and Tis21, respectively.
IFRD1 is member of a gene family that comprises a second gene, IFRD2, also known as SKmc15.
Clinical significance
IFRD1 has been identified as a modifier gene for cystic fibrosisCystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
lung disease.
Biological activity of IFRD1 as 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 MyoDMyoD
MyoD is a protein with a key role in regulating muscle differentiation. MyoD belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 .MyoD is one...
and myogenin
Myogenin
Myogenin , also known as MYOG, is a gene.Myogenin is a muscle-specific basic-helix-loop-helix transcription factor involved in the coordination of skeletal muscle development and repair...
, key master genes of muscle development. 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.
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). The underlying molecular mechanism lies in the ability of IFRD1 to cooperate with MyoD at inducing the transcriptional activity of MEF2C
MEF2C
Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the MEF2C gene. MEF2C is a transcription factor in the Mef2 family.-Genomics:...
. This relies on the ability of IFRD1 to bind selectively MEF2C, thus inhibiting its interaction with HDAC4. Therefore, IFRD1 appears to act as a positive cofactor of MyoD. 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-kB, which is known to inhibit MyoD mRNA accumulation. IFRD1 represses the activity of NF-kB
NF-kB
NF-κB is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens...
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.
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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with several proteins in the SIN3 complex including SIN3B
SIN3B
Paired amphipathic helix protein Sin3b is a protein that in humans is encoded by the SIN3B gene.-Interactions:SIN3B has been shown to interact with HDAC1, Zinc finger and BTB domain-containing protein 16, SUDS3 and IKZF1.-Further reading:...
, SAP30
SAP30
Sin3A-associated protein, 30kDa, also known as SAP30, is a protein which in humans is encoded by the SAP30 gene.- Function :Histone acetylation plays a key role in the regulation of eukaryotic gene expression. Histone acetylation and deacetylation are catalyzed by multisubunit complexes...
, NCOR1
Nuclear receptor co-repressor 1
The nuclear receptor co-repressor 1 also known as thyroid-hormone- and retinoic-acid-receptor-associated co-repressor 1 is a protein that in humans is encoded by the NCOR1 gene....
, and HDAC1
HDAC1
Histone deacetylase 1 is an enzyme that in humans is encoded by the HDAC1 gene.-Interactions:HDAC1 has been shown to interact with RAD9A, DNMT3L, MTA1, FKBP3, CDC20, CDH1, Host cell factor C1, BUB3, Nuclear receptor co-repressor 2, IKZF1, Prohibitin, EVI1, DDX5, DNMT3A, Mothers against...
. Moreover, IFRD1 protein binds MyoD
MyoD
MyoD is a protein with a key role in regulating muscle differentiation. MyoD belongs to a family of proteins known as myogenic regulatory factors . These bHLH transcription factors act sequentially in myogenic differentiation. MRF family members include MyoD, Myf5, myogenin, and MRF4 .MyoD is one...
, MEF2C
MEF2C
Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the MEF2C gene. MEF2C is a transcription factor in the Mef2 family.-Genomics:...
, HDAC4
HDAC4
Histone deacetylase 4, also known as HDAC4, is a protein which in humans is encoded by the HDAC4 gene.- Function :Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects...
, HDAC3
HDAC3
Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,...
and the p65 subunit of NF-kB
NF-kB
NF-κB is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens...
, forming trimolecular complexes with HDAC3
HDAC3
Histone deacetylase 3 is an enzyme that in humans is encoded by the HDAC3 gene.-Interactions:HDAC3 has been shown to interact with HDAC9, HDAC7A, Retinoblastoma protein, RBBP4, Testicular receptor 2, MAP3K7IP2, Peroxisome proliferator-activated receptor delta, GTF2I, Histone deacetylase 5, RELA,...
and p65 NF-kB
NF-kB
NF-κB is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens...
proteins. IFRD1 protein also forms homodimers.