Session: MON 88-111-Cushing's Disease & Non-Functioning Hypothalamus-Pituitary Tumors
Poster Board MON-96
Methods and Results: Mouse AtT20 corticotroph cells were stably transfected with constructs encoding full length human FGFR4 Gly388 (G388) or Arg388 (R388) cDNA. Levels of POMC, glucocorticoid receptor (GR) expression, and phosphorylation of STAT3 (pS-STAT3 and pY-STAT3) were examined after dexamethasone treatment. Compared to controls and FGFR4-R388 cells, FGFR4-WT cells showed enhanced pY-STAT3 responses but significantly decreased GR expression. Fractionation studies revealed diminished nuclear translocation, but not degradation, of the phosphorylated (Ser211) GR. These effects were recapitulated by introducing constitutively active STAT3 mutants. In contrast, FGFR4-R388 cells supported pS-STAT3 which translocates into the mitochondria to enhance basal respiration, drive ATP turnover, increase proton leak, and augment maximal respiration. Using a knock-in mouse model of the FGFR4 SNP we validate altered sensitivity to dexamethasone feedback on corticosterone secretion. Finally, clinical data from 66 patients with ACTH-producing pituitary tumors revealed that those homozygous for the R388 allele showed a higher frequency of silent corticotroph macroadenomas compared to G388 carriers who were more likely to have small microadenomas causing Cushing disease.
Conclusion: Our data demonstrate that the FGFR4 trans-membrane SNP can yield receptor isoforms with differential signaling properties that influence sensitivity to dexamethasone feedback through GR phosphorylation and translocation. Moreover, enhanced pS-STAT3 serves to drive mitochondrial respiratory rate to support the neoplastic growth of corticotroph macroadenomas.
Nothing to Disclose: TT, TT, LZ, MMH, KY, SY, SLA, SZE
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