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AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II))

Identity

Other namesDD3
HA1753
HAKRB
HAKRe
HSD17B5
KIAA0119
hluPGFS
HGNC (Hugo) AKR1C3
LocusID (NCBI) 8644
Location 10p15.1
Location_base_pair Starts at 5090958 and ends at 5149878 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Transcription 1170 bp mRNA; transcript has been detected in brain, lung, liver, small intestine, mammary gland, uterus, prostate, testis.

Protein

Description 323 amino acids, molecular weight 37 kDa.
Expression Activated macrophage, malignant prostate epithelium, normal mammary epithelium, mature blood vessel.
Localisation Mainly in cytoplasm.
Function AKR1C3 metabolizes various androgen metabolites including 5a-dihydrotestosterone to 5a-androstane-3a,17b-diol, Delta4-androstene-3,17-dione to testosterone, androstanedione to 5a-dihydrotestosterone, androsterone to 5a-androstane-3a,17b-diol.
AKR1C3 is also involved in estrogen metabolism converting estrone to 17b-estradiol as well as progesterone metabolism converting prostaglandin D2 to 9a,11b-prostaglandin F2a.
AKR1C3 has the capability of regulating the trans-activation of various nuclear receptors including androgen receptor, estrogen receptor, and peroxisome proliferator activated receptor (PPARG) by regulating the ligand availability for the nuclear receptors.
Homology A member of the of AKR1C family proteins; AKR1C1, AKR1C2, AKR1C3, AKR1C4 in human, and AKR1C9 in rat.

Mutations

Note Mutation of AKR1C3 has not been identified.

Implicated in

Entity Various cancers
Note Elevated levels of AKR1C3 expression are implicated in leukemia cell differentiation, prostate cancer (in both androgen-dependent and androgen-independent prostate cancer), and endometrial cancer. Expression of AKR1C3 was detected in a patient with myelodysplastic syndrome (MDS, refractory anemia) with progression to acute myelogenous leukemia. Overexpression of AKR1C3 in a human promyelocytic leukemia cell line, HL-60, rendered cells more resistant to all-trans retinoic acid (ATRA) and 1a,25-dihydroxyvitamin D3 induced cell differentiation.
  
Entity Prostate cancer
Disease Immunohistochemical staining of human prostate tissues detected negative or low levels of AKR1C3 expression in normal prostate epithelial cells. Strong positive AKR1C3 immunoreactivity was demonstrated in primary and androgen-independent prostate cancers. Variable increases in AKR1C3 expression were also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy, and urothelial cell metaplasia.
  
Entity Endometrial cancer
Disease Quantitative transcriptosome analysis using real-time polymerase chain reaction, AKR1C3 mRNA expression was shown to be elevated in endometrial cancer versus adjacent normal endometrium.
  
Entity Breast tumor
Disease Expression of AKR1C3 mRNA was reduced in breast tumor as compared to adjacent normal breast tissue. Immunohistochemstry revealed that the ductal epithelial cells and stromal cells of the breast express AKR1C3. In myoepithelial cells of the breast, immunoreactive AKR1C3 was absent in normal tissues, whereas strong AKR1C3 staining was apparent in cells surrounding the neoplastic epithelium of ductal carcinoma in situ.
  

External links

Nomenclature
HGNC (Hugo)AKR1C3   386
Entrez_Gene (NCBI)AKR1C3  8644  aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)
Cards
AtlasAKR1C3ID612ch10p15
GeneCards (Weizmann)AKR1C3
Ensembl (Hinxton)ENSG00000196139 [Gene_View]  chr10:5090958-5149878 [Contig_View]  AKR1C3 [Vega]
AceView (NCBI)AKR1C3
Genatlas (Paris)AKR1C3
euGene (Indiana)8644
SOURCE (Stanford)NM_001253908 NM_001253909 NM_003739
Genomic and cartography
GoldenPath (UCSC)AKR1C3  -  10p15.1   chr10:5090958-5149878 +  10p15-p14   [Description]    (hg19-Feb_2009)
EnsemblAKR1C3 - 10p15-p14 [CytoView]
Mapping of homologs : NCBIAKR1C3 [Mapview]
OMIM603966   
Gene and transcription
Genbank (Entrez)AB018580 AF149416 AK290365 AK296701 AK296829
RefSeq transcript (SRS)NM_001253908 NM_001253909 NM_003739
RefSeq transcript (Entrez)NM_001253908 NM_001253909 NM_003739
RefSeq genomic (SRS)AC_000142 NC_000010 NT_008705 NW_001837930
RefSeq genomic (Entrez)AC_000142 NC_000010 NT_008705 NW_001837930
Consensus coding sequences : CCDS (NCBI)AKR1C3
Cluster EST : UnigeneHs.460260 [ SRS ] Hs.460260 [ NCBI ]
Alternative Splicing : Fast-db (Paris)720
Alternative Splicing GalleryENSG00000196139
Gene ExpressionAKR1C3 [ NCBI-GEO ]   AKR1C3 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP42330 (SRS) P42330 (Uniprot)
With graphics : InterProP42330
Splice isoforms : SwissVarP42330(Swissvar)
Domaine pattern : Prosite (SRS)ALDOKETO_REDUCTASE_1 (PS00798)    ALDOKETO_REDUCTASE_2 (PS00062)    ALDOKETO_REDUCTASE_3 (PS00063)   
Domaine pattern : Prosite (Expaxy)ALDOKETO_REDUCTASE_1 (PS00798)    ALDOKETO_REDUCTASE_2 (PS00062)    ALDOKETO_REDUCTASE_3 (PS00063)   
Domains : Interpro (SRS)Aldo/ket_red    Aldo/ket_reductase_CS    Aldo/keto_reductase_subgr    NADP_OxRdtase_dom   
Domains : Interpro (EBI)Aldo/ket_red    Aldo/ket_reductase_CS    Aldo/keto_reductase_subgr    NADP_OxRdtase_dom   
Related proteins : CluSTrP42330
Domain families : Pfam (SRS)Aldo_ket_red (PF00248)   
Domain families : Pfam (Sanger)Aldo_ket_red (PF00248)   
Domain families : Pfam (NCBI)pfam00248   
Blocks (Seattle)P42330
PDB (SRS)1RY0    1RY8    1S1P    1S1R    1S2A    1S2C    1XF0    1ZQ5    2F38    2FGB   
PDB (PDBSum)1RY0    1RY8    1S1P    1S1R    1S2A    1S2C    1XF0    1ZQ5    2F38    2FGB   
PDB (IMB)1RY0    1RY8    1S1P    1S1R    1S2A    1S2C    1XF0    1ZQ5    2F38    2FGB   
PDB (RSDB)1RY0    1RY8    1S1P    1S1R    1S2A    1S2C    1XF0    1ZQ5    2F38    2FGB   
Human Protein AtlasENSG00000196139
HPRD04911
IPIIPI00291483   IPI01014057   
dbDEPCIPI00291483   
Protein Interaction databases
DIP (DOE-UCLA)P42330
IntAct (EBI)P42330
FunCoupENSG00000196139
REACTOMEAKR1C3
BioGRIDAKR1C3
InParanoidP42330
Interologous Interaction database P42330
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)AKR1C3
SNP (GeneSNP Utah)AKR1C3
SNP : HGBaseAKR1C3
Genetic variants : HAPMAPAKR1C3
Somatic Mutations in Cancer : COSMICAKR1C3 
CONAN: Copy Number AnalysisAKR1C3 
Mutations and Diseases : HGMDAKR1C3
OMIM603966   
GENETests603966   
Disease Genetic AssociationAKR1C3
Huge Navigator AKR1C3 [HugePedia]  AKR1C3 [HugeCancerGEM]
Genomic VariantsAKR1C3
snp3D : Map Gene to Disease8644
General knowledge
Homologs : HomoloGeneAKR1C3
Homology/Alignments : Family Browser (UCSC)AKR1C3
Phylogenetic Trees/Animal Genes : TreeFamAKR1C3
Catalytic activity : Enzyme1.-.-.- [ Enzyme-Expasy ]   1.-.-.- [ Enzyme-SRS ]   1.-.-.- [ IntEnz-EBI ]   1.-.-.- [ BRENDA ]   1.-.-.- [ KEGG ]   
Chemical/Protein Interactions : CTD8644
Chemical/Pharm GKB GenePA24679
Clinical trialAKR1C3
Cancer Resource (Charite)ENSG00000196139
Ontology : AmiGOprotein import into nucleus, translocation  retinal dehydrogenase activity  retinoic acid biosynthetic process  alditol:NADP+ 1-oxidoreductase activity  aldo-keto reductase (NADP) activity  retinol dehydrogenase activity  prostaglandin F receptor activity  intracellular  nucleus  cytoplasm  prostaglandin metabolic process  prostaglandin metabolic process  G-protein coupled receptor signaling pathway  response to nutrient  steroid metabolic process  positive regulation of cell proliferation  positive regulation of cell proliferation  male gonad development  cellular response to starvation  positive regulation of cell death  farnesol catabolic process  oxidoreductase activity, acting on NADH or NADPH, quinone or similar compound as acceptor  antibiotic metabolic process  phenanthrene 9,10-monooxygenase activity  keratinocyte differentiation  cellular response to reactive oxygen species  response to prostaglandin stimulus  dihydrotestosterone 17-beta-dehydrogenase activity  progesterone metabolic process  retinal metabolic process  multicellular organismal macromolecule metabolic process  geranylgeranyl reductase activity  ketoreductase activity  prostaglandin-F synthase activity  15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity  androsterone dehydrogenase activity  androsterone dehydrogenase (A-specific) activity  testosterone 17-beta-dehydrogenase (NADP+) activity  ketosteroid monooxygenase activity  trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity  indanol dehydrogenase activity  delta4-3-oxosteroid 5beta-reductase activity  regulation of retinoic acid receptor signaling pathway  testosterone 17-beta-dehydrogenase (NAD+) activity  positive regulation of protein kinase B signaling cascade  oxidation-reduction process  oxidation-reduction process  testosterone biosynthetic process  cellular response to cadmium ion  cellular response to calcium ion  cellular response to prostaglandin stimulus  cellular response to corticosteroid stimulus  cellular response to jasmonic acid stimulus  regulation of testosterone biosynthetic process  positive regulation of endothelial cell apoptosis  positive regulation of reactive oxygen species metabolic process  
Ontology : EGO-EBIprotein import into nucleus, translocation  retinal dehydrogenase activity  retinoic acid biosynthetic process  alditol:NADP+ 1-oxidoreductase activity  aldo-keto reductase (NADP) activity  retinol dehydrogenase activity  prostaglandin F receptor activity  intracellular  nucleus  cytoplasm  prostaglandin metabolic process  prostaglandin metabolic process  G-protein coupled receptor signaling pathway  response to nutrient  steroid metabolic process  positive regulation of cell proliferation  positive regulation of cell proliferation  male gonad development  cellular response to starvation  positive regulation of cell death  farnesol catabolic process  oxidoreductase activity, acting on NADH or NADPH, quinone or similar compound as acceptor  antibiotic metabolic process  phenanthrene 9,10-monooxygenase activity  keratinocyte differentiation  cellular response to reactive oxygen species  response to prostaglandin stimulus  dihydrotestosterone 17-beta-dehydrogenase activity  progesterone metabolic process  retinal metabolic process  multicellular organismal macromolecule metabolic process  geranylgeranyl reductase activity  ketoreductase activity  prostaglandin-F synthase activity  15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity  androsterone dehydrogenase activity  androsterone dehydrogenase (A-specific) activity  testosterone 17-beta-dehydrogenase (NADP+) activity  ketosteroid monooxygenase activity  trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity  indanol dehydrogenase activity  delta4-3-oxosteroid 5beta-reductase activity  regulation of retinoic acid receptor signaling pathway  testosterone 17-beta-dehydrogenase (NAD+) activity  positive regulation of protein kinase B signaling cascade  oxidation-reduction process  oxidation-reduction process  testosterone biosynthetic process  cellular response to cadmium ion  cellular response to calcium ion  cellular response to prostaglandin stimulus  cellular response to corticosteroid stimulus  cellular response to jasmonic acid stimulus  regulation of testosterone biosynthetic process  positive regulation of endothelial cell apoptosis  positive regulation of reactive oxygen species metabolic process  
Pathways : KEGGArachidonic acid metabolismMetabolism of xenobiotics by cytochrome P450
Other databases
Probes
Probes : ImagenesAKR1C3 Related clones (RZPD - Berlin)
Litterature
PubMed101 Pubmed reference(s) in Entrez
PubGeneAKR1C3
iHOPAKR1C3

Bibliography

Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution.
Lin HK, Jez JM, Schlegel BP, Peehl DM, Pachter JA, Penning TM
Molecular endocrinology (Baltimore, Md.). 1997 ; 11 (13) : 1971-1984.
PMID 9415401
 
Localization of type 5 17beta-hydroxysteroid dehydrogenase, 3beta-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry.
El-Alfy M, Luu-The V, Huang XF, Berger L, Labrie F, Pelletier G
Endocrinology. 1999 ; 140 (3) : 1481-1491.
PMID 10067877
 
Immunoelectron microscopic localization of 3beta-hydroxysteroid dehydrogenase and type 5 17beta-hydroxysteroid dehydrogenase in the human prostate and mammary gland.
Pelletier G, Luu-The V, El-Alfy M, Li S, Labrie F
Journal of molecular endocrinology. 2001 ; 26 (1) : 11-19.
PMID 11174850
 
The aldo-keto reductase AKR1C3 is a novel suppressor of cell differentiation that provides a plausible target for the non-cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs.
Desmond JC, Mountford JC, Drayson MT, Walker EA, Hewison M, Ride JP, Luong QT, Hayden RE, Vanin EF, Bunce CM
Cancer research. 2003 ; 63 (2) : 505-512.
PMID 12543809
 
Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling.
Ji Q, Aoyama C, Nien YD, Liu PI, Chen PK, Chang L, Stanczyk FZ, Stolz A
Cancer research. 2004 ; 64 (20) : 7610-7617.
PMID 15492289
 
Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast carcinoma.
Lewis MJ, Wiebe JP, Heathcote JG
BMC cancer. 2004 ; 4 : page 27.
PMID 15212687
 
In situ androgen producing enzymes in human prostate cancer.
Nakamura Y, Suzuki T, Nakabayashi M, Endoh M, Sakamoto K, Mikami Y, Moriya T, Ito A, Takahashi S, Yamada S, Arai Y, Sasano H
Endocrine-related cancer. 2005 ; 12 (1) : 101-107.
PMID 15788642
 
Paracrine-stimulated gene expression profile favors estradiol production in breast tumors.
Amin SA, Huang CC, Reierstad S, Lin Z, Arbieva Z, Wiley E, Saborian H, Haynes B, Cotterill H, Dowsett M, Bulun SE
Molecular and cellular endocrinology. 2006 ; 253 (1-2) : 44-55.
PMID 16735089
 
Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma.
Fung KM, Samara EN, Wong C, Metwalli A, Krlin R, Bane B, Liu CZ, Yang JT, Pitha JV, Culkin DJ, Kropp BP, Penning TM, Lin HK
Endocrine-related cancer. 2006 ; 13 (1) : 169-180.
PMID 16601286
 
Transcriptosome and serum cytokine profiling of an atypical case of myelodysplastic syndrome with progression to acute myelogenous leukemia.
Mahadevan D, DiMento J, Croce KD, Riley C, George B, Fuchs D, Mathews T, Wilson C, Lobell M
American journal of hematology. 2006 ; 81 (10) : 779-786.
PMID 16838325
 
Aldo-keto reductase (AKR) 1C3: role in prostate disease and the development of specific inhibitors.
Penning TM, Steckelbroeck S, Bauman DR, Miller MW, Jin Y, Peehl DM, Fung KM, Lin HK
Molecular and cellular endocrinology. 2006 ; 248 (1-2) : 182-191.
PMID 16417966
 
AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer.
Rizner TL, Smuc T, Rupreht R, Sinkovec J, Penning TM
Molecular and cellular endocrinology. 2006 ; 248 (1-2) : 126-135.
PMID 16338060
 
Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.
Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk SP
Cancer research. 2006 ; 66 (5) : 2815-2825.
PMID 16510604
 
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Contributor(s)

Written11-2007Hsueh Kung Lin
Department of Urology, University of Oklahoma Health Sciences Center, 920 Stanton L Young Blvd, WP3150, Oklahoma City, Oklahoma 73104, USA

Citation

This paper should be referenced as such :
Lin HK . AKR1C3 (aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II)). Atlas Genet Cytogenet Oncol Haematol. November 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/AKR1C3ID612ch10p15.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38539/1/11-2007-AKR1C3ID612ch10p15.pdf   [ Bibliographic record ]

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