title: Thyroid-specific knockout of the tumor suppressor mitogen-inducible gene 6 activates epidermal growth factor receptor signaling pathways and suppresses nuclear factor-κB activity.
abstract: BACKGROUND
  Mitogen-inducible gene 6 (Mig-6) is a putative tumor suppressor gene and prognostic biomarker in papillary thyroid cancer. We hypothesized that Mig-6 knockout would activate pro-oncogenic signaling in mouse thyrocytes.
  
  
  METHODS
  We performed a thyroid-specific knockout using the Cre/loxP recombinase system.
  
  
  RESULTS
  Four knockout and 4 control mouse thyroids were harvested at 2 months of age. Immunoblotting confirmed Mig-6 ablation in knockout mice thyrocytes. Epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation levels were increased in Mig-6 knockout compared to wild-type mice. Total EGFR levels were similar in knockout and wild-type mice. However, EGFR was absent in the caveolae-containing membrane fraction of knockout mice, indicating that Mig-6 depletion is associated with a change in the membrane distribution of EGFR. Although p65 localized to the nucleus in wild-type mice, it was distributed in both cytoplasm and nucleus in knockouts, suggesting that Mig-6 loss decreases p65 activity.
  
  
  CONCLUSIONS
  Our results confirm the feasibility of targeted, thyroid-specific gene knockout as a strategy for studying the relevance of specific genes in thyroid oncogenesis. We suggest that the loss of Mig-6 alters the membrane distribution of EGFR, which may limit receptor degradation and activate this oncogenic signaling pathway.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Chi-Iou
authors.initials: CI
authors.lastname: Lin
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Nehs
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Morris
authors.forename: David B
authors.initials: DB
authors.lastname: Donner
authors.forename: Edward E
authors.initials: EE
authors.lastname: Whang
authors.forename: Jae-wook
authors.initials: JW
authors.lastname: Jeong
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002277:Carcinoma; D002291:Carcinoma, Papillary; D004815:Epidermal Growth Factor / Q000378:metabolism*; D055786:Gene Knockout Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D004815:Epidermal Growth Factor