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

2008-02-01   Leslie Farber , Bin Tean Teh 

Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA

Identity

HGNC
LOCATION
1q31.2
LOCUSID
ALIAS
C1orf28,FIHP,HPTJT,HRPT1,HRPT2,HYX
FUSION GENES

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.

Proteins

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. Parafibromins 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 name
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 name
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 name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
124341542002HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.Carpten JD et al
150709402004Hyperparathyroidism-jaw tumor syndrome in Roma families from Portugal is due to a founder mutation of the HRPT2 gene.Cavaco BM et al
176390622007Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation.Cetani F et al
179231262007Nucleolar localization of parafibromin is mediated by three nucleolar localization signals.Hahn MA et al
154922632004Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.Haven CJ et al
129602102003HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.Howell VM et al
176390632007Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification.Juhlin CC et al
173142752007Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function.Lin L et al
180068352007Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior.Liontos M et al
168178122006Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome.Mizusawa N et al
166308202006Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo.Mosimann C et al
156320632005The parafibromin tumor suppressor protein is part of a human Paf1 complex.Rozenblatt-Rosen O et al
145859402003Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma.Shattuck TM et al
147158342004Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome.Simonds WF et al
160013312005HRPT2, a tumor suppressor gene for hyperparathyroidism-jaw tumor syndrome.Wang PF et al
155802892005Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression.Woodard GE et al
159236222005The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.Yart A et al
169897762006Parafibromin inhibits cancer cell growth and causes G1 phase arrest.Zhang C et al
171308272007Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene.Zhao J et al

Other Information

Locus ID:

NCBI: 79577
MIM: 607393
HGNC: 16783
Ensembl: ENSG00000134371

Variants:

dbSNP: 79577
ClinVar: 79577
TCGA: ENSG00000134371
COSMIC: CDC73

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000134371ENST00000367435Q6P1J9
ENSG00000134371ENST00000635846A0A1B0GUB2
ENSG00000134371ENST00000643006A0A2R8YHB3
ENSG00000134371ENST00000643784A0A2R8Y640
ENSG00000134371ENST00000648071A0A3B3ISN2
ENSG00000134371ENST00000650197A0A3B3IRP5

Expression (GTEx)

0
5
10
15
20
25
30
35

Pathways

PathwaySourceExternal ID
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Signal TransductionREACTOMER-HSA-162582
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Formation of the beta-catenin:TCF transactivating complexREACTOMER-HSA-201722
Signaling by HedgehogREACTOMER-HSA-5358351
Hedgehog 'on' stateREACTOMER-HSA-5632684
Gene ExpressionREACTOMER-HSA-74160
RNA Polymerase II TranscriptionREACTOMER-HSA-73857
RNA Polymerase II Pre-transcription EventsREACTOMER-HSA-674695
RNA Polymerase II Transcription ElongationREACTOMER-HSA-75955
Formation of RNA Pol II elongation complexREACTOMER-HSA-112382
Protein ubiquitinationREACTOMER-HSA-8852135
E3 ubiquitin ligases ubiquitinate target proteinsREACTOMER-HSA-8866654

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
124341542002HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.140
166308202006Parafibromin/Hyrax activates Wnt/Wg target gene transcription by direct association with beta-catenin/Armadillo.111
156320632005The parafibromin tumor suppressor protein is part of a human Paf1 complex.108
191366322009The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3' mRNA processing factors.71
159236222005The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.67
129602102003HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.54
155802892005Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression.45
189873112008The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene.39
200527582010Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors.35
193518172009Genetic mutations associated with cigarette smoking in pancreatic cancer.34

Citation

Leslie Farber ; Bin Tean Teh

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

Atlas Genet Cytogenet Oncol Haematol. 2008-02-01

Online version: http://atlasgeneticsoncology.org/gene/181/cdc73