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CDC73 (cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae))

Identity

Other namesC1orf28
FLJ23316
HPT-JT
HRPT2
HGNC (Hugo) CDC73
LocusID (NCBI) 79577
Location 1q31.2
Location_base_pair Starts at 193091088 and ends at 193223942 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note Defects in CDC73 are the cause of hyperparathyroidism-jaw tumor syndrome. Mutations in CDC73 are also a cause of parathyroid carcinoma (see below).

DNA/RNA

Description 17 exons (all coding)
Transcription CDC73 encodes a 2.7 kb mRNA with a 1596 bp ORF. The transcript has been detected in all tissues tested to date.

Protein

Description 531-amino acid protein (64 kD); termed parafibromin.
Expression Ubiquitously expressed
Localisation Nuclear, bipartite nuclear localization signal
Function CDC73 is a tumor suppressor gene encoding a protein called parafibromin. Parafibromin is a member of the human RNA polymerase II-associated complex, Paf1. The human Paf1 complex is composed of parafibromin, LEO1, PAF1, and CTR9. Parafibromin's interaction with this complex is dependent on its C-terminal domain, which is deleted in ca. 80% of clinically relevant mutations.
Homology Parafibromin shares 54% identity and 67% similarity with the D. melanogaster ortholog and 25% identity and 45% similarity with the C. elegans ortholog. There were no homologies to known protein domains, but moderate identity (32%) and similarity (54%) to the S. cerevisiae ortholog, Cdc73.

Mutations

Germinal Various types of mutations often leading to inactivation of protein
Somatic Various somatic inactivating mutations found in sporadic parathyroid carcinoma

Implicated in

Entity Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT)
Disease HPT-JT is an autosomal dominant, multiple neoplasia syndrome.
Oncogenesis HPT-JT syndrome is primarily characterized by hyperparathyroidism due to parathyroid tumors. Thirty percent of individuals with HPT-JT also develop ossifying fibromas, primarily of the mandible and maxilla, which are distinct from the brown tumors associated with severe hyperparathyroidism. Kidney lesions also occur in HPT-JT as bilateral cysts, renal hamartomas or Wilms tumors.
  
Entity Familial isolated hyperthyroidism
Disease Familial isolated primary hyperparathyroidism is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; or alternatively caused by a distinct entity involving another locus.
  
Entity Sporadic parathyroid carcinoma
Disease These cancers characteristically result in more profound clinical manifestations of hyperparathyroidism than do parathyroid adenomas. Parathyroid carcinomas cause hyperparathyroidism. The hyperparathyroidism is usually severe, with high serum calcium level, severe bone disease, and renal stones.
Prognosis 5-years survival rate is between 50% and 70%.
Oncogenesis Loss of parafibromin expression strongly predicts parathyroid malignancy
  
Entity Sporadic Renal Tumors
Cytogenetics Loss of heterozygosity (LOH) of HRPT2 was found in clear cell , papillary, chromophobe renal cell carcinomas, oncocytomas, and Wilms tumors. In addition, two novel HRPT2 point mutations were detected in clear cell carcinoma and Wilms tumor.
  

External links

Nomenclature
HGNC (Hugo)CDC73   16783
Cards
AtlasCDC73D181ch1q31
Entrez_Gene (NCBI)CDC73  79577  cell division cycle 73
GeneCards (Weizmann)CDC73
Ensembl (Hinxton)ENSG00000134371 [Gene_View]  chr1:193091088-193223942 [Contig_View]  CDC73 [Vega]
AceView (NCBI)CDC73
Genatlas (Paris)CDC73
WikiGenes79577
SOURCE (Princeton)NM_024529
Genomic and cartography
GoldenPath (UCSC)CDC73  -  1q31.2   chr1:193091088-193223942 +  1q25   [Description]    (hg19-Feb_2009)
EnsemblCDC73 - 1q25 [CytoView]
Mapping of homologs : NCBICDC73 [Mapview]
OMIM145000   145001   607393   608266   
Gene and transcription
Genbank (Entrez)AF312865 AI638120 AK026969 AK226038 AK300929
RefSeq transcript (Entrez)NM_024529
RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_012691 NT_004487 NW_001838533 NW_004929293
Consensus coding sequences : CCDS (NCBI)CDC73
Cluster EST : UnigeneHs.378996 [ NCBI ]
CGAP (NCI)Hs.378996
Alternative Splicing : Fast-db (Paris)GSHG0001294
Alternative Splicing GalleryENSG00000134371
Gene ExpressionCDC73 [ NCBI-GEO ]     CDC73 [ SEEK ]   CDC73 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6P1J9 (Uniprot)
NextProtQ6P1J9  [Medical]
With graphics : InterProQ6P1J9
Splice isoforms : SwissVarQ6P1J9 (Swissvar)
Domains : Interpro (EBI)RNA_pol_access_fac_Cdc73   
Related proteins : CluSTrQ6P1J9
Domain families : Pfam (Sanger)CDC73 (PF05179)   
Domain families : Pfam (NCBI)pfam05179   
DMDM Disease mutations79577
Blocks (Seattle)Q6P1J9
Human Protein AtlasENSG00000134371
Peptide AtlasQ6P1J9
HPRD09581
IPIIPI00300659   IPI00909174   
Protein Interaction databases
DIP (DOE-UCLA)Q6P1J9
IntAct (EBI)Q6P1J9
FunCoupENSG00000134371
BioGRIDCDC73
InParanoidQ6P1J9
Interologous Interaction database Q6P1J9
IntegromeDBCDC73
STRING (EMBL)CDC73
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core binding  endodermal cell fate commitment  protein binding  nucleus  transcription, DNA-templated  mRNA polyadenylation  cell cycle  negative regulation of cell proliferation  histone monoubiquitination  Wnt receptor signaling pathway  Cdc73/Paf1 complex  stem cell maintenance  positive regulation of Wnt receptor signaling pathway  positive regulation of mRNA 3'-end processing  protein destabilization  positive regulation of transcription elongation from RNA polymerase II promoter  histone H2B ubiquitination  negative regulation of myeloid cell differentiation  positive regulation of transcription from RNA polymerase II promoter  negative regulation of fibroblast proliferation  negative regulation of epithelial cell proliferation  cellular response to lipopolysaccharide  negative regulation of G1/S transition of mitotic cell cycle  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core binding  endodermal cell fate commitment  protein binding  nucleus  transcription, DNA-templated  mRNA polyadenylation  cell cycle  negative regulation of cell proliferation  histone monoubiquitination  Wnt receptor signaling pathway  Cdc73/Paf1 complex  stem cell maintenance  positive regulation of Wnt receptor signaling pathway  positive regulation of mRNA 3'-end processing  protein destabilization  positive regulation of transcription elongation from RNA polymerase II promoter  histone H2B ubiquitination  negative regulation of myeloid cell differentiation  positive regulation of transcription from RNA polymerase II promoter  negative regulation of fibroblast proliferation  negative regulation of epithelial cell proliferation  cellular response to lipopolysaccharide  negative regulation of G1/S transition of mitotic cell cycle  
REACTOMECDC73
Protein Interaction DatabaseCDC73
Wikipedia pathwaysCDC73
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CDC73
SNP (GeneSNP Utah)CDC73
SNP : HGBaseCDC73
Genetic variants : HAPMAPCDC73
1000_GenomesCDC73 
ICGC programENSG00000134371 
Cancer Gene: CensusCDC73 
Somatic Mutations in Cancer : COSMICCDC73 
CONAN: Copy Number AnalysisCDC73 
Mutations and Diseases : HGMDCDC73
OMIM145000    145001    607393    608266   
GENETestsCDC73
Disease Genetic AssociationCDC73
Huge Navigator CDC73 [HugePedia]  CDC73 [HugeCancerGEM]
Genomic VariantsCDC73  CDC73 [DGVbeta]
Exome VariantCDC73
dbVarCDC73
ClinVarCDC73
snp3D : Map Gene to Disease79577
General knowledge
Homologs : HomoloGeneCDC73
Homology/Alignments : Family Browser (UCSC)CDC73
Phylogenetic Trees/Animal Genes : TreeFamCDC73
Chemical/Protein Interactions : CTD79577
Chemical/Pharm GKB GenePA29464
Clinical trialCDC73
Cancer Resource (Charite)ENSG00000134371
Other databases
Probes
Litterature
PubMed104 Pubmed reference(s) in Entrez
CoreMineCDC73
iHOPCDC73

Bibliography

Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.
Liontos M, Koutsami M, Sideridou M, Evangelou K, Kletsas D, Levy B, Kotsinas A, Nahum O, Zoumpourlis V, Kouloukoussa M, Lygerou Z, Taraviras S, Kittas C, Bartkova J, Papavassiliou AG, Bartek J, Halazonetis TD, Gorgoulis VG
Cancer research. 2007 ; 67 (22) : 10899-10909.
PMID 18006835
 
HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.
Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Hg A, Heath H 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C, Hobbs MR
Nature genetics. 2002 ; 32 (4) : 676-680.
PMID 12434154
 
HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.
Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh DJ, Morreau H, Teh BT
Journal of medical genetics. 2003 ; 40 (9) : 657-663.
PMID 12960210
 
Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma.
Shattuck TM, Vlimki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C, Arnold A
The New England journal of medicine. 2003 ; 349 (18) : 1722-1729.
PMID 14585940
 
Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene.
Cavaco BM, Guerra L, Bradley KJ, Carvalho D, Harding B, Oliveira A, Santos MA, Sobrinho LG, Thakker RV, Leite V
The Journal of clinical endocrinology and metabolism. 2004 ; 89 (4) : 1747-1752.
PMID 15070940
 
Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors.
Cetani F, Pardi E, Borsari S, Viacava P, Dipollina G, Cianferotti L, Ambrogini E, Gazzerro E, Colussi G, Berti P, Miccoli P, Pinchera A, Marcocci C
The Journal of clinical endocrinology and metabolism. 2004 ; 89 (11) : 5583-5591.
PMID 15531515
 
Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.
Haven CJ, Howell VM, Eilers PH, Dunne R, Takahashi M, van Puijenbroek M, Furge K, Kievit J, Tan MH, Fleuren GJ, Robinson BG, Delbridge LW, Philips J, Nelson AE, Krause U, Dralle H, Hoang-Vu C, Gimm O, Morreau H, Marsh DJ, Teh BT
Cancer research. 2004 ; 64 (20) : 7405-7411.
PMID 15492263
 
Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome.
Simonds WF, Robbins CM, Agarwal SK, Hendy GN, Carpten JD, Marx SJ
The Journal of clinical endocrinology and metabolism. 2004 ; 89 (1) : 96-102.
PMID 14715834
 
The parafibromin tumor suppressor protein is part of a human Paf1 complex.
Rozenblatt-Rosen O, Hughes CM, Nannepaga SJ, Shanmugam KS, Copeland TD, Guszczynski T, Resau JH, Meyerson M
Molecular and cellular biology. 2005 ; 25 (2) : 612-620.
PMID 15632063
 
HRPT2, a tumor suppressor gene for hyperparathyroidism-jaw tumor syndrome.
Wang PF, Tan MH, Zhang C, Morreau H, Teh BT
Hormone and metabolic research. Hormon- und Stoffwechselforschung. Hormones et metabolisme. 2005 ; 37 (6) : 380-383.
PMID 16001331
 
Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression.
Woodard GE, Lin L, Zhang JH, Agarwal SK, Marx SJ, Simonds WF
Oncogene. 2005 ; 24 (7) : 1272-1276.
PMID 15580289
 
The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.
Yart A, Gstaiger M, Wirbelauer C, Pecnik M, Anastasiou D, Hess D, Krek W
Molecular and cellular biology. 2005 ; 25 (12) : 5052-5060.
PMID 15923622
 
Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome.
Mizusawa N, Uchino S, Iwata T, Tsuyuguchi M, Suzuki Y, Mizukoshi T, Yamashita Y, Sakurai A, Suzuki S, Beniko M, Tahara H, Fujisawa M, Kamata N, Fujisawa K, Yashiro T, Nagao D, Golam HM, Sano T, Noguchi S, Yoshimoto K
Clinical endocrinology. 2006 ; 65 (1) : 9-16.
PMID 16817812
 
Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo.
Mosimann C, Hausmann G, Basler K
Cell. 2006 ; 125 (2) : 327-341.
PMID 16630820
 
Parafibromin inhibits cancer cell growth and causes G1 phase arrest.
Zhang C, Kong D, Tan MH, Pappas DL Jr, Wang PF, Chen J, Farber L, Zhang N, Koo HM, Weinreich M, Williams BO, Teh BT
Biochemical and biophysical research communications. 2006 ; 350 (1) : 17-24.
PMID 16989776
 
Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation.
Cetani F, Pardi E, Ambrogini E, Viacava P, Borsari S, Lemmi M, Cianferotti L, Miccoli P, Pinchera A, Arnold A, Marcocci C
Endocrine-related cancer. 2007 ; 14 (2) : 493-499.
PMID 17639062
 
Nucleolar localization of parafibromin is mediated by three nucleolar localization signals.
Hahn MA, Marsh DJ
FEBS letters. 2007 ; 581 (26) : 5070-5074.
PMID 17923126
 
Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification.
Juhlin CC, Villablanca A, Sandelin K, Haglund F, Nordenstrm J, Forsberg L, Brnstrm R, Obara T, Arnold A, Larsson C, Hg A
Endocrine-related cancer. 2007 ; 14 (2) : 501-512.
PMID 17639063
 
Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function.
Lin L, Czapiga M, Nini L, Zhang JH, Simonds WF
Molecular cancer research : MCR. 2007 ; 5 (2) : 183-193.
PMID 17314275
 
Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene.
Zhao J, Yart A, Frigerio S, Perren A, Schraml P, Weisstanner C, Stallmach T, Krek W, Moch H
Oncogene. 2007 ; 26 (23) : 3440-3449.
PMID 17130827
 
REVIEW articlesautomatic search in PubMed
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Contributor(s)

Written02-2008Leslie Farber, Bin Tean Teh
Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA

Citation

This paper should be referenced as such :
Farber L, Teh BT . CDC73 (cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)). Atlas Genet Cytogenet Oncol Haematol. February 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/CDC73D181ch1q31.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38594/1/02-2008-CDC73D181ch1q31.pdf   [ Bibliographic record ]

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indexed on : Wed Apr 16 11:19:27 CEST 2014

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