PMID- 22297294
OWN - NLM
STAT- MEDLINE
DCOM- 20120724
LR  - 20211203
IS  - 2041-4889 (Electronic)
VI  - 3
IP  - 2
DP  - 2012 Feb 2
TI  - The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor 
      haploinsufficiency in a parathyroid cancer syndrome.
PG  - 266
LID - 10.1038/cddis.2012.6 [doi]
AB  - Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to 
      the hyperparathyroidism-jaw tumor syndrome associated with a high risk of 
      parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in 
      sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. 
      The molecular pathways that distinguish malignant from benign parathyroid 
      transformation remain elusive. We previously showed that a hypomorphic allele of 
      hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye 
      phenotype of lobe, encoding the fly homolog of Akt1s1/ PRAS40. We report now an 
      interaction between hyx and Tor, a central regulator of cell growth and 
      autophagy, and show that eukaryotic translation initiation factor 4E-binding 
      protein (EIF4EBP), a translational repressor and effector of mammalian target of 
      rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor 
      and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 
      (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation 
      resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell 
      levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, 
      heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 
      by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral 
      marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a 
      model whereby starvation resistance and/or translational de-repression 
      contributes to parathyroid malignant transformation.
FAU - Zhang, J-H
AU  - Zhang JH
AD  - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and 
      Kidney Diseases, National Institute of Allergy and Infectious Diseases, National 
      Institutes of Health, Bethesda, MD, USA.
FAU - Seigneur, E M
AU  - Seigneur EM
FAU - Pandey, M
AU  - Pandey M
FAU - Loshakov, A
AU  - Loshakov A
FAU - Dagur, P K
AU  - Dagur PK
FAU - Connelly, P S
AU  - Connelly PS
FAU - Koo, L
AU  - Koo L
FAU - Panicker, L M
AU  - Panicker LM
FAU - Simonds, W F
AU  - Simonds WF
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20120202
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Biomarkers)
RN  - 0 (CDC73 protein, human)
RN  - 0 (Carrier Proteins)
RN  - 0 (Drosophila Proteins)
RN  - 0 (EIF4EBP3 protein, human)
RN  - 0 (Hyx protein, Drosophila)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Mnn1 protein, Drosophila)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (tor protein, Drosophila)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 4.1.1.- (Carboxy-Lyases)
SB  - IM
MH  - Animals
MH  - Autophagy
MH  - Biomarkers/metabolism
MH  - Carboxy-Lyases/genetics/metabolism
MH  - Carrier Proteins/*genetics/metabolism
MH  - Drosophila Proteins/genetics/metabolism
MH  - Drosophila melanogaster
MH  - Germ-Line Mutation
MH  - Haploinsufficiency
MH  - Heterozygote
MH  - Humans
MH  - Parathyroid Glands/*metabolism/pathology
MH  - Parathyroid Neoplasms/*genetics/metabolism/pathology
MH  - Protein Biosynthesis
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Receptor Protein-Tyrosine Kinases/genetics/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Signal Transduction
MH  - Syndrome
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - Tumor Suppressor Proteins/*genetics/metabolism
PMC - PMC3288348
EDAT- 2012/02/03 06:00
MHDA- 2012/07/25 06:00
PMCR- 2012/02/01
CRDT- 2012/02/03 06:00
PHST- 2012/02/03 06:00 [entrez]
PHST- 2012/02/03 06:00 [pubmed]
PHST- 2012/07/25 06:00 [medline]
PHST- 2012/02/01 00:00 [pmc-release]
AID - cddis20126 [pii]
AID - 10.1038/cddis.2012.6 [doi]
PST - epublish
SO  - Cell Death Dis. 2012 Feb 2;3(2):266. doi: 10.1038/cddis.2012.6.