PPARG (peroxisome proliferator-activated receptor gamma)

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PPARG (peroxisome proliferator-activated receptor gamma)

Identity

Other names PPAR-gamma

NR1C3

PPARG1

PPARG2

HGNC PPARG

Location 3p25.2

Location_base_pair Starts at 12304349 and ends at 12450855 bp from pter ( according to hg18-Mar_2006).

Local_order According to the NCBI map viewer genes flanking PPARG from centromere to telomere are:
TSEN2 3p25.1 tRNA splicing endonuclease 2 homolog (S. cerevisiae)
IQSEC1 3p25.1 IQ motif and Sec7 domain 1
NUP210 3p25.1 nucleoporin 210kDa
TMEM43 3p25.1 transmembrane protein 43

Note The PPAR gamma gene, a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear hormone receptors, is implicated in adipocyte differentiation and function. In order to regulate the transcription of target genes, the PPAR protein needs to form heterodimers with retinoid X receptors (RXRs). Three splice variants of PPAR gamma are known: PPAR gamma1, PPAR gamma2, and PPAR-gamma3. PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Alternatively spliced transcript variants that encode different isoforms have been described.

DNA/RNA

Note The PPAR gamma gene extends over 100kb with 9 exons which gives rise to 3 different PPAR gamma transcripts with differential promoter usage and differential splicing: PPAR gamma 1, 2 and 3. PPAR gamma 1 transcript contains 8 exons which is 97% identical to PPAR gamma 2.

Genomic structure of the 5 primed end of the human PPAR gamma gene. All three subtypes have the exons 1-6. PPAR gamma1 contains in addition the exons A1 and A2 both of which are untranslated, PPAR gamma2 contains exon B, which is translated, and PPAR gamma3 contains only the untranslated exon A2.

Description According to Entrez-Gene, PPAR gamma gene maps to NC_000003 and spans a region of 100 kilo bases. According to Spidey, PPAR gamma 1 has 8 exons, the sizes being 171, 74, 228, 170, 139, 200, 451 and 459 bps. PPAR gamma 2 has 7 exons, the sizes being 173, 228, 170, 139, 200, 451 and 459. PPAR Gamma 3 has 8 exons, the sizes being 198, 74, 228, 170, 139, 200, 451, and 459.

Transcription PPAR gamma 1 mRNA (NM_138712) has a size of 1892 bp, PPAR gamma 2 mRNA (NM_015869) has a size of 1820 bp while PPAR gamma 3 mRNA (NM_138711) has a size of 1919 bp.
The ratio of PPAR gamma2 to PPAR gamma1 transcript has been shown to increase in obese patients in correlation with their body mass indices. A low calorie diet was specifically shown to down-regulate the expression of PPAR gamma2 mRNA in adipose tissue of obese humans. However, this effect was lost subsequently during weight maintenance.
The PPAR gamma3 mRNA is transcribed from a novel promoter localized 5' of exon A2 (see diagram above). PPARgamma3 mRNA expression is said to be restricted to human white adipocytes, as well as in HepG2, Caco-2 and HeLa cell lines.

Pseudogene No pseudogene has been reported for PPAR gamma.

Protein

Note There are 3 different PPAR gamma proteins PPAR gamma 1, 2 and 3 which differ at their 5-prime ends, each under the control of its own promoter. PPAR gamma1 and PPAR gamma3, however, give rise to the same protein, encoded by exons 1 through 6, because neither the A1 nor the A2 exons are translated.

Description The PPAR gamma protein consists of 505 amino acids and has a molecular weight of 57.6 kDa. According to the NCBI conserved domain search, it contains two C4 type zinc finger domains. In nearly all cases, this is the DNA binding domain of a nuclear hormone receptor. In addition it contains a ligand binding domain. This all-helical domain is involved in binding the hormone to these receptors.

The various domains of PPAR gamma protein with their specific functions. Post transcriptional modifications indicating functional changes have been depicted.

Expression In general, the highest expression of PPAR gamma can be found in the adipose tissue, colonic epithelia, macrophages, and endothelium, followed by the kidney, liver, and small intestine; whereas PPAR gamma can barely be detected in the muscle.
Of the splice variants, PPAR gamma1 and gamma2 are expressed in adipose tissue. PPAR gamma1 expression levels were lower than gamma2 in the liver and heart, whereas both gamma1 and gamma2 were expressed in skeletal muscle at low levels.
The expression of PPAR gamma3 mRNA is restricted to adipose tissue and differentiated CaCo2 cells.

Localisation Localized in the nucleus.

Function Protein-protein interactions PPARs function as heterodimers with retinoid receptor (RXR). The PPARRXR heterodimer function along with co-activators such as NCOA6, NCOA7 or PPARBP, leading to increases in transcription of target genes.
PPAR gamma1 or PPAR gamma 2 in a heterodimer with RXR is capable of forming complexes with oligonucleotides containing peroxisome proliferator response elements (PPREs) usually 5'-AACT AGGNCA A AGGTCA-3' in the promoter regions of the target genes. PPAR gamma1 and PPAR gamma2 can also form complexes with RXRB and RXRG.
Ligands of PPAR gamma PPAR gamma1 and PPAR gamma2 have ligand-dependent and -independent activation domains. Due to the presence of an additional 28 amino acids at the amino terminus, PPAR gamma2 has a ligand-independent activation domain that is several folds more effective than that of PPAR gamma1. However, in the presence of ligands that can be lipid derivatives, eicosanoids, xenobiotics etc, triggers a conformational change in the protein that results in the recruitment of transcriptional co-activators. In the absence of a ligand, PPAR gamma is bound to transcriptional co-repressors containing nuclear receptor corepressor ( N-CoR ) and can actively silence the transcription of target genes.
Phosphorylation of serine 112 at the N terminus of PPAR gamma2 results in a reduction of its transcriptional activity. This phosphorylation further promotes the sumoylation of lysine 107 which then further reduces its transcriptional activity.
The prostaglandin J2 (PGJ2) metabolite l5-deoxy-Delta12,14-PGJ2 binds directly to PPAR gamma and can promotes the differentiation of C3HlOT1/2 fibroblasts to adipocytes. Its principal function came to light when it was found that the anti-diabetic drug thiazolidinediones (TZD) was a PPAR gamma ligand. The TZD series of drugs via their agonist activity on PPAR gamma promotes the uptake of circulating fatty acids into adipocytes. The glucose lowering effects of TZDs are due to increased disposal of glucose into adipose tissues along with increased expression of insulin sensitizing factors (such as adiponectin) and decreased expression of proteins that promote insulin resistance.
PPAR gamma also has an anti-inflammatory role by inhibiting the production of inflammatory cytokines, and other proteins such as TNF-alpha, MMP9 and iNOS from macrophages in the presence of ligands such as TZD. Inhibition of pro-inflammatory transcription factors such as NF-kB, AP-1 and STAT by PPAR gamma is said to be through limited availability of shared co-factors as well as direct protein-protein interactions.

Homology Canis familiaris PPARG peroxisome proliferator-activated receptor gamma
Pan troglodytes PPARG peroxisome proliferator-activated receptor gamma
Rattus norvegicus Pparg peroxisome proliferator-activated receptor gamma
Mus musculus Pparg peroxisome proliferator-activated receptor gamma

Mutations

Note Several mutations in the PPAR gamma protein have been reported along with their association with diseased states.
1. P115Q results in severe obesity
2. 1-BP DEL, 472A, Q286P, K319TER and R288H mutations have been reported in somatic colon cancer
3. P467L, V290M mutations have been reported in partial familial lipodystrophy type 3
4. 3-BP DEL/1-BP INS, NT553, shown in digenic insulin resistance.

Implicated in

Entity Metabolic syndrome

Note Metabolic syndrome is a very common condition that is associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. In obese and diabetic rodents thiazolidinediones (TZDs), known to be a potent PPAR gamma ligand, are mostly used to alleviate elevated plasma glucose levels and they are known to be efficacious therapeutic agents for the treatment of noninsulin-dependent diabetes mellitus (NIDDM). TZD derivatives can also increase the insulin sensitivity of target tissues in animal models of NIDDM. The antidiabetic effects of TZDs are thought to be mediated by means of transactivation of PPAR gamma 1 and 2.
A commonly found polymorphism of PPAR gamma, P12A, is associated with decreased risk of type 2 diabetes.
An alternative activation of macrophages has been implicated in the atheroprotective effects of PPAR gamma. PPAR gamma is critical for the formation of a subpopulation of "alternatively activated" macrophages which exert their anti-inflammatory properties via paracrine effects on "classically activated" (M1) macrophages within the atherosclerotic lesion. In addition, oxidized low density lipoproteins (LDL), but not normal LDL, reduce the expression of proinflammatory cytokines in LPS stimulated macrophages presumably through their effect on PPAR gamma.

Entity Familial Partial Lipodystrophy Type 3

Note In a study including patients with hyperinsulinemia and early-onset hypertension, patients have been shown to have dominant-negative mutations in PPAR gamma proteins. The dominant negative effect is characterized with a proline to leucine (P467L) mutation in the PPAR gamma protein. Patients with these mutations showed symptoms of severe peripheral and hepatic insulin resistance, partial lipodystrophy and abnormal functioning of adipose tissue.

Entity Breast Cancer

Note In human primary and metastatic breast cancers it has been shown that there are significant levels of PPAR gamma expression. Cell culture studies have indicated that in the presence of the PPAR gamma ligand TZD, cells have undergone differentiation, lost the malignant phenotype and showed a decrease in the proliferation rate. This was associated with the accumulation of lipids and subsequent change in the expression profile.

Entity Prostate Cancer

Note PPAR gamma expression has been shown in human prostate adenocarcinomas and corresponding cell lines and specific ligands have been found to decrease the proliferation in these cancer cells by indusing PPAR gamma activation. From these data, it has been concluded that PPAR gamma might have a therapeutic potential in prostate cancer by acting as a biological modifier.

Entity Colorectal Cancer

Note Mouse colon treated with PPAR gamma ligands was shown to increase the expression level of beta-catenin protein. In addition, protein-protein interaction was observed between beta-catenin and PPARgamma in cultured cell lines and colonic epithelium in mice. Thus, ligand-activated PPARgamma interacts with beta-catenin, thereby retaining it in the cytosol and reducing beta-catenin/T cell factor transcriptional activity that is required for aberrant crypt foci (ACF) formation. Short-term exposure to dietary PPAR gamma ligands such as linoleic acid and conjugated linoleic acid has been shown to inhibit colon cancer metastasis.

Entity Lung cancer

Note PPAR gamma ligands have been shown to decrease the proliferation of non small cell lung cancer (NSCLC) cell lines and xenograft models. Forced overexpression of PPAR gamma in a NSCLC cell line model inhibited the expression of COX-2 protein and promoter activity, resulting in decreased prostaglandin E2 production. The increased activity of the PTEN homologue caused a decrease in the level of phosphor-AKT and the resulting inhibition of NF-kB was implicated in the inhibition of COX-2 expression.

Entity T-Cell Leukaemia

Note In T-cell leukaemia, the PPAR gamma ligand Prostaglandin D(2) (PGD(2)) which is highly produced in mast cells, platelets, and alveolar macrophages, has antiproliferative effects. On the other hand these prostaglandins have no effect in normal human T cells. Similar actions were observed in the presence of ciglitazone and troglitazone. All of these ligands are thought to be antiapoptotic and exerting their function in a PPAR gamma dependent manner.

Entity Pituitary Tumours

Note PPAR gamma ligands have been shown to induce G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumour cells . In adrenocorticotrophic hormone (ACTH)-secreting pituitary tumours, there is high morbidity associated with excessive glucocorticoid production. The PPAR gamma ligand, rosiglitazone, prevented tumour formation of subcutaneously injected At20 cells secreting ACTH murine corticotroph cells.

External links

Nomenclature
HGNC PPARG   9236

Entrez_Gene PPARG  5468  peroxisome proliferator-activated receptor gamma

Cards
Atlas PPARGID383ch3p25

GeneCards PPARG

Ensembl ENSG00000132170 [Gene_View]  PPARG [Vega]

Genatlas PPARG
Genomic and cartography
GoldenPath PPARG - 3p25.2   chr3:12304349-12450855 + 3p25   [Description]    (hg18-Mar_2006)

Ensembl PPARG - 3p25 [CytoView]
NCBI Mapview

OMIM 137800 Disease map [OMIM]

OMIM 151660 Disease map [OMIM]

OMIM 601487 Disease map [OMIM]

OMIM 601665 Disease map [OMIM]

OMIM 604367 Disease map [OMIM]

OMIM 609830 Disease map [OMIM]

HomoloGene PPARG

Gene and transcription
Genbank AB097931 [ ENTREZ ]

Genbank AB107271 [ ENTREZ ]

Genbank AJ563369 [ ENTREZ ]

Genbank AJ563370 [ ENTREZ ]

Genbank AJ698135 [ ENTREZ ]

RefSeq NM_005037 [ SRS ]    NM_005037 [ ENTREZ ]

RefSeq NM_015869 [ SRS ]    NM_015869 [ ENTREZ ]

RefSeq NM_138711 [ SRS ]    NM_138711 [ ENTREZ ]

RefSeq NM_138712 [ SRS ]    NM_138712 [ ENTREZ ]

RefSeq AC_000046 [ SRS ]    AC_000046 [ ENTREZ ]

RefSeq AC_000135 [ SRS ]    AC_000135 [ ENTREZ ]

RefSeq NC_000003 [ SRS ]    NC_000003 [ ENTREZ ]

RefSeq NT_022517 [ SRS ]    NT_022517 [ ENTREZ ]

RefSeq NW_001838877 [ SRS ]    NW_001838877 [ ENTREZ ]

RefSeq NW_921651 [ SRS ]    NW_921651 [ ENTREZ ]

CCDS PPARG CCDS - NCBI

AceView PPARG AceView - NCBI

Unigene Hs.162646 [ SRS ]    Hs.162646 [ NCBI ]

Fast-db 2173 (alternative variants)

Protein : pattern, domain, 3D structure
SwissProt P37231 [ SRS]    P37231 [ EXPASY ]     P37231 [ INTERPRO ]     P37231 [ UNIPROT ] P37231 [ VarSplice FASTA ]

Prosite PS00031 NUCLEAR_REC_DBD_1 [ SRS ]    PS00031 NUCLEAR_REC_DBD_1 [ Expasy ]

Prosite PS51030 NUCLEAR_REC_DBD_2 [ SRS ]    PS51030 NUCLEAR_REC_DBD_2 [ Expasy ]

Interpro IPR003074 1Cnucl_rcpt [ SRS ]    IPR003074 1Cnucl_rcpt [ EBI ]

Interpro IPR003077 1Cnucl_rcpt_G [ SRS ]    IPR003077 1Cnucl_rcpt_G [ EBI ]

Interpro IPR008946 Nucl_hormone_rcpt_ligand-bd [ SRS ]    IPR008946 Nucl_hormone_rcpt_ligand-bd [ EBI ]

Interpro IPR000536 Nucl_hrmn_rcpt_lig-bd_core [ SRS ]    IPR000536 Nucl_hrmn_rcpt_lig-bd_core [ EBI ]

Interpro IPR001723 Str_hrmn_rcpt [ SRS ]    IPR001723 Str_hrmn_rcpt [ EBI ]

Interpro IPR001628 Znf_hrmn_rcpt [ SRS ]    IPR001628 Znf_hrmn_rcpt [ EBI ]

Interpro IPR013088 Znf_NHR/GATA [ SRS ]    IPR013088 Znf_NHR/GATA [ EBI ]

CluSTr P37231

Pfam PF00104 Hormone_recep [ SRS ]    PF00104 Hormone_recep [ Sanger ]    pfam00104 [ NCBI-CDD ]

Pfam PF00105 zf-C4 [ SRS ]    PF00105 zf-C4 [ Sanger ]    pfam00105 [ NCBI-CDD ]

Smart SM00430 HOLI [EMBL]

Smart SM00399 ZnF_C4 [EMBL]

Prodom PD000035 Znf_C4steroid[INRA-Toulouse]

Prodom P37231 PPARG_HUMAN [ Domain structure ]   P37231 PPARG_HUMAN [ sequences sharing at least 1 domain ]

Blocks P37231

PDB 1FM6 [ SRS ]    1FM6 [ PdbSum ],   1FM6 [ IMB ]   1FM6 [ RSDB ]

PDB 1FM9 [ SRS ]    1FM9 [ PdbSum ],   1FM9 [ IMB ]   1FM9 [ RSDB ]

PDB 1I7I [ SRS ]    1I7I [ PdbSum ],   1I7I [ IMB ]   1I7I [ RSDB ]

PDB 1K74 [ SRS ]    1K74 [ PdbSum ],   1K74 [ IMB ]   1K74 [ RSDB ]

PDB 1KNU [ SRS ]    1KNU [ PdbSum ],   1KNU [ IMB ]   1KNU [ RSDB ]

PDB 1NYX [ SRS ]    1NYX [ PdbSum ],   1NYX [ IMB ]   1NYX [ RSDB ]

PDB 1PRG [ SRS ]    1PRG [ PdbSum ],   1PRG [ IMB ]   1PRG [ RSDB ]

PDB 1RDT [ SRS ]    1RDT [ PdbSum ],   1RDT [ IMB ]   1RDT [ RSDB ]

PDB 1WM0 [ SRS ]    1WM0 [ PdbSum ],   1WM0 [ IMB ]   1WM0 [ RSDB ]

PDB 1ZEO [ SRS ]    1ZEO [ PdbSum ],   1ZEO [ IMB ]   1ZEO [ RSDB ]

PDB 1ZGY [ SRS ]    1ZGY [ PdbSum ],   1ZGY [ IMB ]   1ZGY [ RSDB ]

PDB 2ATH [ SRS ]    2ATH [ PdbSum ],   2ATH [ IMB ]   2ATH [ RSDB ]

PDB 2F4B [ SRS ]    2F4B [ PdbSum ],   2F4B [ IMB ]   2F4B [ RSDB ]

PDB 2FVJ [ SRS ]    2FVJ [ PdbSum ],   2FVJ [ IMB ]   2FVJ [ RSDB ]

PDB 2G0G [ SRS ]    2G0G [ PdbSum ],   2G0G [ IMB ]   2G0G [ RSDB ]

PDB 2G0H [ SRS ]    2G0H [ PdbSum ],   2G0H [ IMB ]   2G0H [ RSDB ]

PDB 2GTK [ SRS ]    2GTK [ PdbSum ],   2GTK [ IMB ]   2GTK [ RSDB ]

PDB 2HFP [ SRS ]    2HFP [ PdbSum ],   2HFP [ IMB ]   2HFP [ RSDB ]

PDB 2HWQ [ SRS ]    2HWQ [ PdbSum ],   2HWQ [ IMB ]   2HWQ [ RSDB ]

PDB 2HWR [ SRS ]    2HWR [ PdbSum ],   2HWR [ IMB ]   2HWR [ RSDB ]

PDB 2I4J [ SRS ]    2I4J [ PdbSum ],   2I4J [ IMB ]   2I4J [ RSDB ]

PDB 2I4P [ SRS ]    2I4P [ PdbSum ],   2I4P [ IMB ]   2I4P [ RSDB ]

PDB 2I4Z [ SRS ]    2I4Z [ PdbSum ],   2I4Z [ IMB ]   2I4Z [ RSDB ]

PDB 2OM9 [ SRS ]    2OM9 [ PdbSum ],   2OM9 [ IMB ]   2OM9 [ RSDB ]

PDB 2P4Y [ SRS ]    2P4Y [ PdbSum ],   2P4Y [ IMB ]   2P4Y [ RSDB ]

PDB 2POB [ SRS ]    2POB [ PdbSum ],   2POB [ IMB ]   2POB [ RSDB ]

PDB 2PRG [ SRS ]    2PRG [ PdbSum ],   2PRG [ IMB ]   2PRG [ RSDB ]

PDB 2Q59 [ SRS ]    2Q59 [ PdbSum ],   2Q59 [ IMB ]   2Q59 [ RSDB ]

PDB 2Q5P [ SRS ]    2Q5P [ PdbSum ],   2Q5P [ IMB ]   2Q5P [ RSDB ]

PDB 2Q5S [ SRS ]    2Q5S [ PdbSum ],   2Q5S [ IMB ]   2Q5S [ RSDB ]

PDB 2Q61 [ SRS ]    2Q61 [ PdbSum ],   2Q61 [ IMB ]   2Q61 [ RSDB ]

PDB 2Q6R [ SRS ]    2Q6R [ PdbSum ],   2Q6R [ IMB ]   2Q6R [ RSDB ]

PDB 2Q6S [ SRS ]    2Q6S [ PdbSum ],   2Q6S [ IMB ]   2Q6S [ RSDB ]

PDB 3PRG [ SRS ]    3PRG [ PdbSum ],   3PRG [ IMB ]   3PRG [ RSDB ]

PDB 4PRG [ SRS ]    4PRG [ PdbSum ],   4PRG [ IMB ]   4PRG [ RSDB ]

HPRD 03288

Protein Interaction databases
DIP P37231
IntAct P37231
Polymorphism : SNP, mutations, diseases
OMIM 137800    [ map ]

OMIM 151660    [ map ]

OMIM 601487    [ map ]

OMIM 601665    [ map ]

OMIM 604367    [ map ]

OMIM 609830    [ map ]

GENETests 137800

GENETests 151660

GENETests 601487

GENETests 601665

GENETests 604367

GENETests 609830

SNP PPARG [dbSNP-NCBI]

SNP NM_005037 [SNP-NCI]
SNP NM_015869 [SNP-NCI]
SNP NM_138711 [SNP-NCI]
SNP NM_138712 [SNP-NCI]
SNP PPARG [GeneSNPs - Utah]  PPARG] [HGBASE - SRS]

HAPMAP PPARG [HAPMAP]

COSMIC PPARG [Somatic mutation (COSMIC-CGP-Sanger)]
TICdb PPARG [Translocation breakpoints In Cancer]
HGMD PPARG

Genetic Association PPARG

CDC HuGE PPARG

General knowledge
Family Browser PPARG [UCSC Family Browser]

SOURCE NM_005037

SOURCE NM_015869

SOURCE NM_138711

SOURCE NM_138712

SMD Hs.162646

SAGE Hs.162646

GO negative regulation of transcription from RNA polymerase II promoter [Amigo]  negative regulation of transcription from RNA polymerase II promoter

GO placenta development [Amigo]  placenta development

GO DNA binding [Amigo]  DNA binding

GO transcription factor activity [Amigo]  transcription factor activity

GO steroid hormone receptor activity [Amigo]  steroid hormone receptor activity

GO receptor activity [Amigo]  receptor activity

GO ligand-dependent nuclear receptor activity [Amigo]  ligand-dependent nuclear receptor activity

GO prostaglandin receptor activity [Amigo]  prostaglandin receptor activity

GO nucleus [Amigo]  nucleus

GO cytosol [Amigo]  cytosol

GO transcription [Amigo]  transcription

GO regulation of transcription, DNA-dependent [Amigo]  regulation of transcription, DNA-dependent

GO lipid metabolic process [Amigo]  lipid metabolic process

GO signal transduction [Amigo]  signal transduction

GO response to nutrient [Amigo]  response to nutrient

GO drug binding [Amigo]  drug binding

GO regulation of blood pressure [Amigo]  regulation of blood pressure

GO zinc ion binding [Amigo]  zinc ion binding

GO long-chain fatty acid transport [Amigo]  long-chain fatty acid transport

GO transcription activator activity [Amigo]  transcription activator activity

GO transcription repressor activity [Amigo]  transcription repressor activity

GO monocyte differentiation [Amigo]  monocyte differentiation

GO epithelial cell differentiation [Amigo]  epithelial cell differentiation

GO cellular response to insulin stimulus [Amigo]  cellular response to insulin stimulus

GO transcription activator binding [Amigo]  transcription activator binding

GO response to lipid [Amigo]  response to lipid

GO glucose homeostasis [Amigo]  glucose homeostasis

GO lipoprotein transport [Amigo]  lipoprotein transport

GO sequence-specific DNA binding [Amigo]  sequence-specific DNA binding

GO innate immune response [Amigo]  innate immune response

GO cell fate commitment [Amigo]  cell fate commitment

GO positive regulation of fat cell differentiation [Amigo]  positive regulation of fat cell differentiation

GO low-density lipoprotein receptor biosynthetic process [Amigo]  low-density lipoprotein receptor biosynthetic process

GO positive regulation of transcription from RNA polymerase II promoter [Amigo]  positive regulation of transcription from RNA polymerase II promoter

GO metal ion binding [Amigo]  metal ion binding

GO retinoid X receptor binding [Amigo]  retinoid X receptor binding

GO protein heterodimerization activity [Amigo]  protein heterodimerization activity

GO cell maturation [Amigo]  cell maturation

GO arachidonic acid binding [Amigo]  arachidonic acid binding

GO white fat cell differentiation [Amigo]  white fat cell differentiation

GO lipid homeostasis [Amigo]  lipid homeostasis

GO response to low density lipoprotein stimulus [Amigo]  response to low density lipoprotein stimulus

BIOCARTA Nuclear Receptors in Lipid Metabolism and Toxicity    [Genes]

BIOCARTA Basic mechanism of action of PPARa, PPARb(d) and PPARg and effects on gene expression    [Genes]

BIOCARTA Role of PPAR-gamma Coactivators in Obesity and Thermogenesis    [Genes]

BIOCARTA Visceral Fat Deposits and the Metabolic Syndrome    [Genes]

KEGG PPAR signaling pathway

PubGene PPARG

TreeFam PPARG

CTD 5468 [Comparative ToxicoGenomics Database]

Other databases
Probes
Probe PPARG Related clones (RZPD - Berlin)

PubMed
PubMed 499 Pubmed reference(s) in Entrez

	Nomenclature
HGNC	PPARG 9236
Entrez_Gene	PPARG 5468 peroxisome proliferator-activated receptor gamma
	Cards
Atlas	PPARGID383ch3p25
GeneCards	PPARG
Ensembl	ENSG00000132170 [Gene_View] PPARG [Vega]
Genatlas	PPARG
	Genomic and cartography
GoldenPath	PPARG - 3p25.2 chr3:12304349-12450855 + 3p25 [Description] (hg18-Mar_2006)
Ensembl	PPARG - 3p25 [CytoView]
NCBI	Mapview
OMIM	137800 Disease map [OMIM]
OMIM	151660 Disease map [OMIM]
OMIM	601487 Disease map [OMIM]
OMIM	601665 Disease map [OMIM]
OMIM	604367 Disease map [OMIM]
OMIM	609830 Disease map [OMIM]
HomoloGene	PPARG
	Gene and transcription
Genbank	AB097931 [ ENTREZ ]
Genbank	AB107271 [ ENTREZ ]
Genbank	AJ563369 [ ENTREZ ]
Genbank	AJ563370 [ ENTREZ ]
Genbank	AJ698135 [ ENTREZ ]
RefSeq	NM_005037 [ SRS ] NM_005037 [ ENTREZ ]
RefSeq	NM_015869 [ SRS ] NM_015869 [ ENTREZ ]
RefSeq	NM_138711 [ SRS ] NM_138711 [ ENTREZ ]
RefSeq	NM_138712 [ SRS ] NM_138712 [ ENTREZ ]
RefSeq	AC_000046 [ SRS ] AC_000046 [ ENTREZ ]
RefSeq	AC_000135 [ SRS ] AC_000135 [ ENTREZ ]
RefSeq	NC_000003 [ SRS ] NC_000003 [ ENTREZ ]
RefSeq	NT_022517 [ SRS ] NT_022517 [ ENTREZ ]
RefSeq	NW_001838877 [ SRS ] NW_001838877 [ ENTREZ ]
RefSeq	NW_921651 [ SRS ] NW_921651 [ ENTREZ ]
CCDS	PPARG CCDS - NCBI
AceView	PPARG AceView - NCBI
Unigene	Hs.162646 [ SRS ] Hs.162646 [ NCBI ]
Fast-db	2173 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P37231 [ SRS] P37231 [ EXPASY ] P37231 [ INTERPRO ] P37231 [ UNIPROT ] P37231 [ VarSplice FASTA ]
Prosite	PS00031 NUCLEAR_REC_DBD_1 [ SRS ] PS00031 NUCLEAR_REC_DBD_1 [ Expasy ]
Prosite	PS51030 NUCLEAR_REC_DBD_2 [ SRS ] PS51030 NUCLEAR_REC_DBD_2 [ Expasy ]
Interpro	IPR003074 1Cnucl_rcpt [ SRS ] IPR003074 1Cnucl_rcpt [ EBI ]
Interpro	IPR003077 1Cnucl_rcpt_G [ SRS ] IPR003077 1Cnucl_rcpt_G [ EBI ]
Interpro	IPR008946 Nucl_hormone_rcpt_ligand-bd [ SRS ] IPR008946 Nucl_hormone_rcpt_ligand-bd [ EBI ]
Interpro	IPR000536 Nucl_hrmn_rcpt_lig-bd_core [ SRS ] IPR000536 Nucl_hrmn_rcpt_lig-bd_core [ EBI ]
Interpro	IPR001723 Str_hrmn_rcpt [ SRS ] IPR001723 Str_hrmn_rcpt [ EBI ]
Interpro	IPR001628 Znf_hrmn_rcpt [ SRS ] IPR001628 Znf_hrmn_rcpt [ EBI ]
Interpro	IPR013088 Znf_NHR/GATA [ SRS ] IPR013088 Znf_NHR/GATA [ EBI ]
CluSTr	P37231
Pfam	PF00104 Hormone_recep [ SRS ] PF00104 Hormone_recep [ Sanger ] pfam00104 [ NCBI-CDD ]
Pfam	PF00105 zf-C4 [ SRS ] PF00105 zf-C4 [ Sanger ] pfam00105 [ NCBI-CDD ]
Smart	SM00430 HOLI [EMBL]
Smart	SM00399 ZnF_C4 [EMBL]
Prodom	PD000035 Znf_C4steroid[INRA-Toulouse]
Prodom	P37231 PPARG_HUMAN [ Domain structure ] P37231 PPARG_HUMAN [ sequences sharing at least 1 domain ]
Blocks	P37231
PDB	1FM6 [ SRS ] 1FM6 [ PdbSum ], 1FM6 [ IMB ] 1FM6 [ RSDB ]
PDB	1FM9 [ SRS ] 1FM9 [ PdbSum ], 1FM9 [ IMB ] 1FM9 [ RSDB ]
PDB	1I7I [ SRS ] 1I7I [ PdbSum ], 1I7I [ IMB ] 1I7I [ RSDB ]
PDB	1K74 [ SRS ] 1K74 [ PdbSum ], 1K74 [ IMB ] 1K74 [ RSDB ]
PDB	1KNU [ SRS ] 1KNU [ PdbSum ], 1KNU [ IMB ] 1KNU [ RSDB ]
PDB	1NYX [ SRS ] 1NYX [ PdbSum ], 1NYX [ IMB ] 1NYX [ RSDB ]
PDB	1PRG [ SRS ] 1PRG [ PdbSum ], 1PRG [ IMB ] 1PRG [ RSDB ]
PDB	1RDT [ SRS ] 1RDT [ PdbSum ], 1RDT [ IMB ] 1RDT [ RSDB ]
PDB	1WM0 [ SRS ] 1WM0 [ PdbSum ], 1WM0 [ IMB ] 1WM0 [ RSDB ]
PDB	1ZEO [ SRS ] 1ZEO [ PdbSum ], 1ZEO [ IMB ] 1ZEO [ RSDB ]
PDB	1ZGY [ SRS ] 1ZGY [ PdbSum ], 1ZGY [ IMB ] 1ZGY [ RSDB ]
PDB	2ATH [ SRS ] 2ATH [ PdbSum ], 2ATH [ IMB ] 2ATH [ RSDB ]
PDB	2F4B [ SRS ] 2F4B [ PdbSum ], 2F4B [ IMB ] 2F4B [ RSDB ]
PDB	2FVJ [ SRS ] 2FVJ [ PdbSum ], 2FVJ [ IMB ] 2FVJ [ RSDB ]
PDB	2G0G [ SRS ] 2G0G [ PdbSum ], 2G0G [ IMB ] 2G0G [ RSDB ]
PDB	2G0H [ SRS ] 2G0H [ PdbSum ], 2G0H [ IMB ] 2G0H [ RSDB ]
PDB	2GTK [ SRS ] 2GTK [ PdbSum ], 2GTK [ IMB ] 2GTK [ RSDB ]
PDB	2HFP [ SRS ] 2HFP [ PdbSum ], 2HFP [ IMB ] 2HFP [ RSDB ]
PDB	2HWQ [ SRS ] 2HWQ [ PdbSum ], 2HWQ [ IMB ] 2HWQ [ RSDB ]
PDB	2HWR [ SRS ] 2HWR [ PdbSum ], 2HWR [ IMB ] 2HWR [ RSDB ]
PDB	2I4J [ SRS ] 2I4J [ PdbSum ], 2I4J [ IMB ] 2I4J [ RSDB ]
PDB	2I4P [ SRS ] 2I4P [ PdbSum ], 2I4P [ IMB ] 2I4P [ RSDB ]
PDB	2I4Z [ SRS ] 2I4Z [ PdbSum ], 2I4Z [ IMB ] 2I4Z [ RSDB ]
PDB	2OM9 [ SRS ] 2OM9 [ PdbSum ], 2OM9 [ IMB ] 2OM9 [ RSDB ]
PDB	2P4Y [ SRS ] 2P4Y [ PdbSum ], 2P4Y [ IMB ] 2P4Y [ RSDB ]
PDB	2POB [ SRS ] 2POB [ PdbSum ], 2POB [ IMB ] 2POB [ RSDB ]
PDB	2PRG [ SRS ] 2PRG [ PdbSum ], 2PRG [ IMB ] 2PRG [ RSDB ]
PDB	2Q59 [ SRS ] 2Q59 [ PdbSum ], 2Q59 [ IMB ] 2Q59 [ RSDB ]
PDB	2Q5P [ SRS ] 2Q5P [ PdbSum ], 2Q5P [ IMB ] 2Q5P [ RSDB ]
PDB	2Q5S [ SRS ] 2Q5S [ PdbSum ], 2Q5S [ IMB ] 2Q5S [ RSDB ]
PDB	2Q61 [ SRS ] 2Q61 [ PdbSum ], 2Q61 [ IMB ] 2Q61 [ RSDB ]
PDB	2Q6R [ SRS ] 2Q6R [ PdbSum ], 2Q6R [ IMB ] 2Q6R [ RSDB ]
PDB	2Q6S [ SRS ] 2Q6S [ PdbSum ], 2Q6S [ IMB ] 2Q6S [ RSDB ]
PDB	3PRG [ SRS ] 3PRG [ PdbSum ], 3PRG [ IMB ] 3PRG [ RSDB ]
PDB	4PRG [ SRS ] 4PRG [ PdbSum ], 4PRG [ IMB ] 4PRG [ RSDB ]
HPRD	03288
	Protein Interaction databases
DIP	P37231
IntAct	P37231
	Polymorphism : SNP, mutations, diseases
OMIM	137800 [ map ]
OMIM	151660 [ map ]
OMIM	601487 [ map ]
OMIM	601665 [ map ]
OMIM	604367 [ map ]
OMIM	609830 [ map ]
GENETests	137800
GENETests	151660
GENETests	601487
GENETests	601665
GENETests	604367
GENETests	609830
SNP	PPARG [dbSNP-NCBI]
SNP	NM_005037 [SNP-NCI]
SNP	NM_015869 [SNP-NCI]
SNP	NM_138711 [SNP-NCI]
SNP	NM_138712 [SNP-NCI]
SNP	PPARG [GeneSNPs - Utah] PPARG] [HGBASE - SRS]
HAPMAP	PPARG [HAPMAP]
COSMIC	PPARG [Somatic mutation (COSMIC-CGP-Sanger)]
TICdb	PPARG [Translocation breakpoints In Cancer]
HGMD	PPARG
Genetic Association	PPARG
CDC HuGE	PPARG
	General knowledge
Family Browser	PPARG [UCSC Family Browser]
SOURCE	NM_005037
SOURCE	NM_015869
SOURCE	NM_138711
SOURCE	NM_138712
SMD	Hs.162646
SAGE	Hs.162646
GO	negative regulation of transcription from RNA polymerase II promoter [Amigo] negative regulation of transcription from RNA polymerase II promoter
GO	placenta development [Amigo] placenta development
GO	DNA binding [Amigo] DNA binding
GO	transcription factor activity [Amigo] transcription factor activity
GO	steroid hormone receptor activity [Amigo] steroid hormone receptor activity
GO	receptor activity [Amigo] receptor activity
GO	ligand-dependent nuclear receptor activity [Amigo] ligand-dependent nuclear receptor activity
GO	prostaglandin receptor activity [Amigo] prostaglandin receptor activity
GO	nucleus [Amigo] nucleus
GO	cytosol [Amigo] cytosol
GO	transcription [Amigo] transcription
GO	regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA-dependent
GO	lipid metabolic process [Amigo] lipid metabolic process
GO	signal transduction [Amigo] signal transduction
GO	response to nutrient [Amigo] response to nutrient
GO	drug binding [Amigo] drug binding
GO	regulation of blood pressure [Amigo] regulation of blood pressure
GO	zinc ion binding [Amigo] zinc ion binding
GO	long-chain fatty acid transport [Amigo] long-chain fatty acid transport
GO	transcription activator activity [Amigo] transcription activator activity
GO	transcription repressor activity [Amigo] transcription repressor activity
GO	monocyte differentiation [Amigo] monocyte differentiation
GO	epithelial cell differentiation [Amigo] epithelial cell differentiation
GO	cellular response to insulin stimulus [Amigo] cellular response to insulin stimulus
GO	transcription activator binding [Amigo] transcription activator binding
GO	response to lipid [Amigo] response to lipid
GO	glucose homeostasis [Amigo] glucose homeostasis
GO	lipoprotein transport [Amigo] lipoprotein transport
GO	sequence-specific DNA binding [Amigo] sequence-specific DNA binding
GO	innate immune response [Amigo] innate immune response
GO	cell fate commitment [Amigo] cell fate commitment
GO	positive regulation of fat cell differentiation [Amigo] positive regulation of fat cell differentiation
GO	low-density lipoprotein receptor biosynthetic process [Amigo] low-density lipoprotein receptor biosynthetic process
GO	positive regulation of transcription from RNA polymerase II promoter [Amigo] positive regulation of transcription from RNA polymerase II promoter
GO	metal ion binding [Amigo] metal ion binding
GO	retinoid X receptor binding [Amigo] retinoid X receptor binding
GO	protein heterodimerization activity [Amigo] protein heterodimerization activity
GO	cell maturation [Amigo] cell maturation
GO	arachidonic acid binding [Amigo] arachidonic acid binding
GO	white fat cell differentiation [Amigo] white fat cell differentiation
GO	lipid homeostasis [Amigo] lipid homeostasis
GO	response to low density lipoprotein stimulus [Amigo] response to low density lipoprotein stimulus
BIOCARTA	Nuclear Receptors in Lipid Metabolism and Toxicity [Genes]
BIOCARTA	Basic mechanism of action of PPARa, PPARb(d) and PPARg and effects on gene expression [Genes]
BIOCARTA	Role of PPAR-gamma Coactivators in Obesity and Thermogenesis [Genes]
BIOCARTA	Visceral Fat Deposits and the Metabolic Syndrome [Genes]
KEGG	PPAR signaling pathway
PubGene	PPARG
TreeFam	PPARG
CTD	5468 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	PPARG Related clones (RZPD - Berlin)
	PubMed
PubMed	499 Pubmed reference(s) in Entrez

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Prostaglandin D2, its metabolite 15-d-PGJ2, and peroxisome proliferator activated receptor-gamma agonists induce apoptosis in transformed, but not normal, human T lineage cells.

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Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas.

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Contributor(s)

Written 07-2008 Erhan Astarci, Sreeparna Banerjee

Department of Biological Sciences, Middle East Technical University, Ankara 06531 Turkey

Citation

This paper should be referenced as such :
Astarci E, Banerjee S . PPARG (peroxisome proliferator-activated receptor gamma). Atlas Genet Cytogenet Oncol Haematol. July 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/PPARGID383ch3p25.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Nov 27 13:27:43 2008

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For comments and suggestions or contributions, please contact us
jlhuret@AtlasGeneticsOncology.org.

Other names	PPAR-gamma
	NR1C3
	PPARG1
	PPARG2
HGNC	PPARG
Location	3p25.2
Location_base_pair	Starts at 12304349 and ends at 12450855 bp from pter ( according to hg18-Mar_2006).
Local_order	According to the NCBI map viewer genes flanking PPARG from centromere to telomere are: TSEN2 3p25.1 tRNA splicing endonuclease 2 homolog (S. cerevisiae) IQSEC1 3p25.1 IQ motif and Sec7 domain 1 NUP210 3p25.1 nucleoporin 210kDa TMEM43 3p25.1 transmembrane protein 43

Note	The PPAR gamma gene extends over 100kb with 9 exons which gives rise to 3 different PPAR gamma transcripts with differential promoter usage and differential splicing: PPAR gamma 1, 2 and 3. PPAR gamma 1 transcript contains 8 exons which is 97% identical to PPAR gamma 2.


	Genomic structure of the 5 primed end of the human PPAR gamma gene. All three subtypes have the exons 1-6. PPAR gamma1 contains in addition the exons A1 and A2 both of which are untranslated, PPAR gamma2 contains exon B, which is translated, and PPAR gamma3 contains only the untranslated exon A2.

Description	According to Entrez-Gene, PPAR gamma gene maps to NC_000003 and spans a region of 100 kilo bases. According to Spidey, PPAR gamma 1 has 8 exons, the sizes being 171, 74, 228, 170, 139, 200, 451 and 459 bps. PPAR gamma 2 has 7 exons, the sizes being 173, 228, 170, 139, 200, 451 and 459. PPAR Gamma 3 has 8 exons, the sizes being 198, 74, 228, 170, 139, 200, 451, and 459.
Transcription	PPAR gamma 1 mRNA (NM_138712) has a size of 1892 bp, PPAR gamma 2 mRNA (NM_015869) has a size of 1820 bp while PPAR gamma 3 mRNA (NM_138711) has a size of 1919 bp. The ratio of PPAR gamma2 to PPAR gamma1 transcript has been shown to increase in obese patients in correlation with their body mass indices. A low calorie diet was specifically shown to down-regulate the expression of PPAR gamma2 mRNA in adipose tissue of obese humans. However, this effect was lost subsequently during weight maintenance. The PPAR gamma3 mRNA is transcribed from a novel promoter localized 5' of exon A2 (see diagram above). PPARgamma3 mRNA expression is said to be restricted to human white adipocytes, as well as in HepG2, Caco-2 and HeLa cell lines.
Pseudogene	No pseudogene has been reported for PPAR gamma.

Note	There are 3 different PPAR gamma proteins PPAR gamma 1, 2 and 3 which differ at their 5-prime ends, each under the control of its own promoter. PPAR gamma1 and PPAR gamma3, however, give rise to the same protein, encoded by exons 1 through 6, because neither the A1 nor the A2 exons are translated.

Description	The PPAR gamma protein consists of 505 amino acids and has a molecular weight of 57.6 kDa. According to the NCBI conserved domain search, it contains two C4 type zinc finger domains. In nearly all cases, this is the DNA binding domain of a nuclear hormone receptor. In addition it contains a ligand binding domain. This all-helical domain is involved in binding the hormone to these receptors.


	The various domains of PPAR gamma protein with their specific functions. Post transcriptional modifications indicating functional changes have been depicted.

Expression	In general, the highest expression of PPAR gamma can be found in the adipose tissue, colonic epithelia, macrophages, and endothelium, followed by the kidney, liver, and small intestine; whereas PPAR gamma can barely be detected in the muscle. Of the splice variants, PPAR gamma1 and gamma2 are expressed in adipose tissue. PPAR gamma1 expression levels were lower than gamma2 in the liver and heart, whereas both gamma1 and gamma2 were expressed in skeletal muscle at low levels. The expression of PPAR gamma3 mRNA is restricted to adipose tissue and differentiated CaCo2 cells.
Localisation	Localized in the nucleus.
Function	Protein-protein interactions PPARs function as heterodimers with retinoid receptor (RXR). The PPARRXR heterodimer function along with co-activators such as NCOA6, NCOA7 or PPARBP, leading to increases in transcription of target genes. PPAR gamma1 or PPAR gamma 2 in a heterodimer with RXR is capable of forming complexes with oligonucleotides containing peroxisome proliferator response elements (PPREs) usually 5'-AACT AGGNCA A AGGTCA-3' in the promoter regions of the target genes. PPAR gamma1 and PPAR gamma2 can also form complexes with RXRB and RXRG. Ligands of PPAR gamma PPAR gamma1 and PPAR gamma2 have ligand-dependent and -independent activation domains. Due to the presence of an additional 28 amino acids at the amino terminus, PPAR gamma2 has a ligand-independent activation domain that is several folds more effective than that of PPAR gamma1. However, in the presence of ligands that can be lipid derivatives, eicosanoids, xenobiotics etc, triggers a conformational change in the protein that results in the recruitment of transcriptional co-activators. In the absence of a ligand, PPAR gamma is bound to transcriptional co-repressors containing nuclear receptor corepressor ( N-CoR ) and can actively silence the transcription of target genes. Phosphorylation of serine 112 at the N terminus of PPAR gamma2 results in a reduction of its transcriptional activity. This phosphorylation further promotes the sumoylation of lysine 107 which then further reduces its transcriptional activity. The prostaglandin J2 (PGJ2) metabolite l5-deoxy-Delta12,14-PGJ2 binds directly to PPAR gamma and can promotes the differentiation of C3HlOT1/2 fibroblasts to adipocytes. Its principal function came to light when it was found that the anti-diabetic drug thiazolidinediones (TZD) was a PPAR gamma ligand. The TZD series of drugs via their agonist activity on PPAR gamma promotes the uptake of circulating fatty acids into adipocytes. The glucose lowering effects of TZDs are due to increased disposal of glucose into adipose tissues along with increased expression of insulin sensitizing factors (such as adiponectin) and decreased expression of proteins that promote insulin resistance. PPAR gamma also has an anti-inflammatory role by inhibiting the production of inflammatory cytokines, and other proteins such as TNF-alpha, MMP9 and iNOS from macrophages in the presence of ligands such as TZD. Inhibition of pro-inflammatory transcription factors such as NF-kB, AP-1 and STAT by PPAR gamma is said to be through limited availability of shared co-factors as well as direct protein-protein interactions.
Homology	Canis familiaris PPARG peroxisome proliferator-activated receptor gamma Pan troglodytes PPARG peroxisome proliferator-activated receptor gamma Rattus norvegicus Pparg peroxisome proliferator-activated receptor gamma Mus musculus Pparg peroxisome proliferator-activated receptor gamma

Entity	Metabolic syndrome
Note	Metabolic syndrome is a very common condition that is associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. In obese and diabetic rodents thiazolidinediones (TZDs), known to be a potent PPAR gamma ligand, are mostly used to alleviate elevated plasma glucose levels and they are known to be efficacious therapeutic agents for the treatment of noninsulin-dependent diabetes mellitus (NIDDM). TZD derivatives can also increase the insulin sensitivity of target tissues in animal models of NIDDM. The antidiabetic effects of TZDs are thought to be mediated by means of transactivation of PPAR gamma 1 and 2. A commonly found polymorphism of PPAR gamma, P12A, is associated with decreased risk of type 2 diabetes. An alternative activation of macrophages has been implicated in the atheroprotective effects of PPAR gamma. PPAR gamma is critical for the formation of a subpopulation of "alternatively activated" macrophages which exert their anti-inflammatory properties via paracrine effects on "classically activated" (M1) macrophages within the atherosclerotic lesion. In addition, oxidized low density lipoproteins (LDL), but not normal LDL, reduce the expression of proinflammatory cytokines in LPS stimulated macrophages presumably through their effect on PPAR gamma.

Entity	Familial Partial Lipodystrophy Type 3
Note	In a study including patients with hyperinsulinemia and early-onset hypertension, patients have been shown to have dominant-negative mutations in PPAR gamma proteins. The dominant negative effect is characterized with a proline to leucine (P467L) mutation in the PPAR gamma protein. Patients with these mutations showed symptoms of severe peripheral and hepatic insulin resistance, partial lipodystrophy and abnormal functioning of adipose tissue.

Entity	Breast Cancer
Note	In human primary and metastatic breast cancers it has been shown that there are significant levels of PPAR gamma expression. Cell culture studies have indicated that in the presence of the PPAR gamma ligand TZD, cells have undergone differentiation, lost the malignant phenotype and showed a decrease in the proliferation rate. This was associated with the accumulation of lipids and subsequent change in the expression profile.

Entity	Prostate Cancer
Note	PPAR gamma expression has been shown in human prostate adenocarcinomas and corresponding cell lines and specific ligands have been found to decrease the proliferation in these cancer cells by indusing PPAR gamma activation. From these data, it has been concluded that PPAR gamma might have a therapeutic potential in prostate cancer by acting as a biological modifier.

Entity	Colorectal Cancer
Note	Mouse colon treated with PPAR gamma ligands was shown to increase the expression level of beta-catenin protein. In addition, protein-protein interaction was observed between beta-catenin and PPARgamma in cultured cell lines and colonic epithelium in mice. Thus, ligand-activated PPARgamma interacts with beta-catenin, thereby retaining it in the cytosol and reducing beta-catenin/T cell factor transcriptional activity that is required for aberrant crypt foci (ACF) formation. Short-term exposure to dietary PPAR gamma ligands such as linoleic acid and conjugated linoleic acid has been shown to inhibit colon cancer metastasis.

Entity	Lung cancer
Note	PPAR gamma ligands have been shown to decrease the proliferation of non small cell lung cancer (NSCLC) cell lines and xenograft models. Forced overexpression of PPAR gamma in a NSCLC cell line model inhibited the expression of COX-2 protein and promoter activity, resulting in decreased prostaglandin E2 production. The increased activity of the PTEN homologue caused a decrease in the level of phosphor-AKT and the resulting inhibition of NF-kB was implicated in the inhibition of COX-2 expression.

Entity	T-Cell Leukaemia
Note	In T-cell leukaemia, the PPAR gamma ligand Prostaglandin D(2) (PGD(2)) which is highly produced in mast cells, platelets, and alveolar macrophages, has antiproliferative effects. On the other hand these prostaglandins have no effect in normal human T cells. Similar actions were observed in the presence of ciglitazone and troglitazone. All of these ligands are thought to be antiapoptotic and exerting their function in a PPAR gamma dependent manner.

Entity	Pituitary Tumours
Note	PPAR gamma ligands have been shown to induce G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumour cells . In adrenocorticotrophic hormone (ACTH)-secreting pituitary tumours, there is high morbidity associated with excessive glucocorticoid production. The PPAR gamma ligand, rosiglitazone, prevented tumour formation of subcutaneously injected At20 cells secreting ACTH murine corticotroph cells.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Written	07-2008	Erhan Astarci, Sreeparna Banerjee
		Department of Biological Sciences, Middle East Technical University, Ankara 06531 Turkey