The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome.
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.
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.
J-H
JH
Zhang
E M
EM
Seigneur
M
M
Pandey
A
A
Loshakov
P K
PK
Dagur
P S
PS
Connelly
L
L
Koo
L M
LM
Panicker
W F
WF
Simonds
D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D018095:Germ-Line Mutation; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D010280:Parathyroid Glands / Q000378:metabolism* / Q000473:pathology; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013577:Syndrome; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; C454900:CDC73 protein, human; D002352:Carrier Proteins; D029721:Drosophila Proteins; C112661:EIF4EBP3 protein, human; C508978:Hyx protein, Drosophila; C105373:MEN1 protein, human; C499857:Mnn1 protein, Drosophila; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D020794:Receptor Protein-Tyrosine Kinases; C080148:tor protein, Drosophila; D058570:TOR Serine-Threonine Kinases; D002262:Carboxy-Lyases