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

Identity

Other names	C1orf28
	FLJ23316
	HPT-JT
	HRPT2
HGNC	CDC73
Location	1q31.2

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	CDC73   16783
Entrez_Gene	CDC73  79577  cell division cycle 73, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)
	Cards
Atlas	CDC73D181ch1q31
GeneCards	CDC73
Ensembl	CDC73 [Search_View]   ENSG00000134371 [Gene_View]
Genatlas	CDC73
GeneLynx	CDC73
eGenome	CDC73
euGene	79577
	Genomic and cartography
GoldenPath	CDC73  -  1q31.2   chr1:191357784-191487679 +  1q25   [Description]    (hg18-Mar_2006)
Ensembl	CDC73 - 1q25 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	CDC73
	Gene and transcription
Genbank	AF312865 [ ENTREZ ]
Genbank	AK026969 [ ENTREZ ]
Genbank	AK226038 [ ENTREZ ]
Genbank	AK314772 [ ENTREZ ]
Genbank	BC007325 [ ENTREZ ]
RefSeq	NM_024529 [ SRS ]    NM_024529 [ ENTREZ ]
RefSeq	AC_000044 [ SRS ]    AC_000044 [ ENTREZ ]
RefSeq	AC_000133 [ SRS ]    AC_000133 [ ENTREZ ]
RefSeq	NC_000001 [ SRS ]    NC_000001 [ ENTREZ ]
RefSeq	NT_004487 [ SRS ]    NT_004487 [ ENTREZ ]
RefSeq	NW_001838533 [ SRS ]    NW_001838533 [ ENTREZ ]
RefSeq	NW_926128 [ SRS ]    NW_926128 [ ENTREZ ]
AceView	CDC73 AceView - NCBI
Unigene	Hs.576497 [ SRS ]    Hs.576497 [ NCBI ]     HS576497 [ spliceNest ]
Fast-db	17668 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q6P1J9 [ SRS]    Q6P1J9 [ EXPASY ]     Q6P1J9 [ INTERPRO ]     Q6P1J9 [ UNIPROT ]
Interpro	IPR007852 RNA_pol_access_fac_Cdc73 [ SRS ]    IPR007852 RNA_pol_access_fac_Cdc73 [ EBI ]
CluSTr	Q6P1J9
Pfam	PF05179 CDC73 [ SRS ]    PF05179 CDC73 [ Sanger ]    pfam05179 [ NCBI-CDD ]
Blocks	Q6P1J9
HPRD	09581
	Protein Interaction databases
DIP	Q6P1J9
IntAct	Q6P1J9
	Polymorphism : SNP, mutations, diseases
OMIM	145000;145001;607393;608266    [ map ]
GENECLINICS	145000;145001;607393;608266
SNP	CDC73 [dbSNP-NCBI]
SNP	NM_024529 [SNP-NCI]
SNP	CDC73 [GeneSNPs - Utah]  CDC73] [HGBASE - SRS]
HAPMAP	CDC73 [HAPMAP]
COSMIC	CDC73 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	CDC73
	General knowledge
Family Browser	CDC73 [UCSC Family Browser]
SOURCE	NM_024529
SMD	Hs.576497
SAGE	Hs.576497
GO	protein binding [Amigo]  protein binding
GO	nucleus [Amigo]  nucleus
GO	transcription [Amigo]  transcription
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
PubGene	CDC73
TreeFam	CDC73
CTD	79577 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	CDC73 Related clones (RZPD - Berlin)
	PubMed
PubMed	47 Pubmed reference(s) in LocusLink

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, H����g 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, V��lim��ki 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, Nordenstr��m J, Forsberg L, Br��nstr��m R, Obara T, Arnold A, Larsson C, H����g 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 articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	02-2008	Leslie 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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:12:51 2008