PPARGC1A
Encyclopedia
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) is a protein
that in humans is encoded by the PPARGC1A gene
.
PPARGC1A is also known as human accelerated region
20. It may, therefore, have played a key role in differentiating humans from apes.
PGC-1alpha is a transcriptional coactivator
that regulates the genes involved in energy metabolism. This protein interacts with the nuclear receptor
PPAR-γ, which permits the interaction of this protein with multiple transcription factor
s. This protein can interact with, and regulate the activities of, cAMP response element-binding protein (CREB
) and nuclear respiratory factors (NRFs)
. It provides a direct link between external physiological stimuli and the regulation of mitochondrial
biogenesis, and is a major factor that regulates muscle fiber type determination. Endurance exercise has been shown to activate the PGC-1alpha gene in human skeletal muscle This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.
It is known to be activated by a host of factors, including:
conferring protective effects on mitochondrial metabolism.
with:
ERRalpha and PGC-1alpha are coactivators of both Glucokinase (GK) and SIRT3
, binding to an ERRE
elements in the GK and SIRT3 promoters.
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 PPARGC1A 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...
.
PPARGC1A is also known as human accelerated region
Human accelerated regions
Human accelerated regions , first described in August 2006, are a set of 49 segments of the human genome which are conserved throughout vertebrate evolution but are strikingly different in humans. They are named HAR1 through HAR49 according to their degree of difference between humans and chimpanzees...
20. It may, therefore, have played a key role in differentiating humans from apes.
PGC-1alpha is a transcriptional coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
that regulates the genes involved in energy metabolism. This protein interacts with the nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
PPAR-γ, which permits the interaction of this protein with multiple transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. This protein can interact with, and regulate the activities of, cAMP response element-binding protein (CREB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
) and nuclear respiratory factors (NRFs)
NRF1
Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis,...
. It provides a direct link between external physiological stimuli and the regulation of mitochondrial
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
biogenesis, and is a major factor that regulates muscle fiber type determination. Endurance exercise has been shown to activate the PGC-1alpha gene in human skeletal muscle This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.
Regulation
PGC-1α is thought to be a master integrator of external signals.It is known to be activated by a host of factors, including:
- Reactive oxygen species (ROS)Reactive oxygen speciesReactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
and reactive nitrogen species (RNS)Reactive nitrogen speciesReactive nitrogen species are a family of antimicrobial molecules derived from nitric oxide and superoxide produced via the enzymatic activity of inducible nitric oxide synthase 2 and NADPH oxidase respectively...
, both formed endogenously in the cell as by-products of metabolism but upregulated during times of cellular stress. - cAMP response element-binding (CREBCREBCREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
) proteins, activated by an increase in cAMP following external cellular signals. - Protein kinase B / AktAKTAkt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
is thought to downregulate PGC-1α, but upregulate its downstream effectors, NRF1 and NRF2. Akt itself is activated by PIP3, often upregulated by IP3K after G-protein signals. The Akt family is also known to activate pro-survival signals as well as metabolic activation. - SIRT1 binds and activates PGC-1α through deacetylation.
Clinical significance
Recently PPARGC1A has been implicated as a potential therapy for Parkinson's DiseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
conferring protective effects on mitochondrial metabolism.
Interactions
PPARGC1A 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:
- CREB-binding protein
- Farnesoid X receptorFarnesoid X receptorThe bile acid receptor , also known as farnesoid X receptor or NR1H4 is a nuclear receptor that is encoded by the NR1H4 gene in humans.- Function :...
- FBXW7FBXW7F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.-Interactions:FBXW7 has been shown to interact with PPARGC1A, Parkin , MYB and SKP1A.-Further reading:...
- MED1MED1Mediator of RNA polymerase II transcription subunit 1 is a protein that in humans is encoded by the MED1 gene.- Function :The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with...
MED12MED12Mediator of RNA polymerase II transcription, subunit 12 homolog , also known as MED12, is a human gene found on the X chromosome...
MED14MED14Mediator of RNA polymerase II transcription subunit 14 is an enzyme that in humans is encoded by the MED14 gene.-Interactions:MED14 has been shown to interact with PPARGC1A, Estrogen receptor alpha, STAT2, Cyclin-dependent kinase 8, Glucocorticoid receptor and Hepatocyte nuclear factor 4...
MED17MED17Mediator of RNA polymerase II transcription subunit 17 is an enzyme that in humans is encoded by the MED17 gene.-Interactions:MED17 has been shown to interact with PPARGC1A, Cyclin-dependent kinase 8 and BRCA1.-Further reading:... - NRF1NRF1Nuclear respiratory factor 1, also known as Nrf1, Nrf-1, NRF1 and NRF-1, encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis,...
- Peroxisome proliferator-activated receptor gammaPeroxisome proliferator-activated receptor gammaPeroxisome proliferator-activated receptor gamma , also known as the glitazone receptor, or NR1C3 is a type II nuclear receptor that in humans is encoded by the PPARG gene.Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 and...
- Retinoid X receptor alphaRetinoid X receptor alphaRetinoid X receptor alpha , also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.- Function :...
. - Thyroid hormone receptor betaThyroid hormone receptor betaThyroid hormone receptor beta also known as nuclear receptor subfamily 1, group A, member 2 , is a nuclear receptor protein that in humans is encoded by the THRB gene.- Function :...
ERRalpha and PGC-1alpha are coactivators of both Glucokinase (GK) and SIRT3
SIRT3
NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein...
, binding to an ERRE
Erre
-References:*...
elements in the GK and SIRT3 promoters.