Abstract
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.
Highlights
Despite its strong association with parathyroid cancer, inactivation of CDC73 is quite rare in sporadic, benign parathyroid tumors.[16,17] In contrast, inactivation of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene is nearly always associated with benign parathyroid tumors in the context of familial or sporadic MEN1,18 and somatic inactivation of MEN1 in sporadic benign parathyroid tumors is common.[19,20] Despite the identification of these key parathyroid tumor suppressor genes, the mechanisms and pathways that distinguish benign from malignant transformation of the parathyroid remain elusive
Gene expression profiling studies of parathyroid tumors by Haven et al.[39] strongly suggest that sporadic parathyroid malignancies and tumors associated with CDC73 inactivation follow a pathway distinct from benign sporadic and MEN1related parathyroid tumors
This dichotomy is reinforced by the clinical observations that inactivation of CDC73 is frequent in parathyroid cancer,[8,9] but rare in sporadic benign parathyroid tumors,[16,17] whereas mutation of MEN1 is nearly always associated with benign parathyroid adenomas in both sporadic and MEN1-associated cases
Summary
Despite its strong association with parathyroid cancer, inactivation of CDC73 is quite rare in sporadic, benign parathyroid tumors.[16,17] In contrast, inactivation of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene is nearly always associated with benign parathyroid tumors in the context of familial or sporadic MEN1,18 and somatic inactivation of MEN1 in sporadic benign parathyroid tumors is common.[19,20] Despite the identification of these key parathyroid tumor suppressor genes, the mechanisms and pathways that distinguish benign from malignant transformation of the parathyroid remain elusive. One well-characterized effector of mTOR is the eukaryotic translation initiation factor 4E-binding protein (eIF4EBP or 4E-BP) that competes with eIF-4G for binding to eIF-4E to inhibit mRNA cap-dependent translational initiation.[27,28] Phosphorylation of eIF4EBP by mTOR reduces its affinity for eIF-4E and promotes the initiation of protein synthesis from a pool of transcripts enriched in mRNAs encoding proteins involved in angiogenesis, growth, and survival.[29] Enhanced function of eIF-4E, often a result of inactivation of eIF4EBP by phosphorylation, is linked to poor prognosis, tumor progression, and metastasis in squamous cell,[30] breast,[31,32] ovarian, 33 and other cancers
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