title: Growth hormone and insulin-like growth factor I insensitivity of fibroblasts isolated from a patient with an I{kappa}B{alpha} mutation.
abstract: BACKGROUND
  NF-kappaB is a family of transcription factors involved in cell proliferation, differentiation, and apoptosis.
  
  
  OBJECTIVE
  We have recently demonstrated that NF-kappaB is expressed in the growth plate and it mediates the growth-promoting effects of IGF-I on chondrogenesis and longitudinal bone growth. Humans with defects of the NF-kappaB pathway exhibit growth failure, which suggests a possible regulatory role for NF-kappaB in statural growth. We have previously reported a child with ectodermal dysplasia, immunodeficiency, and growth retardation, harboring a heterozygous mutation of IkappaBalpha, an essential component of the NF-kappaB pathway. Since he was found with low IGF-l and IGFBP-3, and elevated GH secretion, an IGF-l generation test was carried out: baseline IGF-l was low and only responded to a high dose of GH. Thus, the diagnosis of GH resistance was made.
  
  
  RESULTS
  To assess the underlying mechanisms of his GH resistance, we cultured the patient's skin fibroblasts with GH and/or IGF-I. While both GH and IGF-l induced cell proliferation and NF-kappaB activity in controls' fibroblasts, they had no effect on the patient's fibroblasts. In the fibroblasts of the patient's father (who displays mosaicism for the IkappaBalpha mutation), GH and IGF-l elicited an attenuated stimulatory effect. In addition, GH stimulated STAT5 phosphorylation and IGF-l mRNA expression in controls ' and the father's fibroblasts, while IGF-l induced PI3K activity and mRNA and protein expression of TDAG51, a target gene for IGF-I. In contrast, none of these effects was elicited by GH or IGF-l in the patient's fibroblasts.
  
  
  CONCLUSIONS
  Our findings suggest that this patient's IkappaBalpha mutation caused GH and IGF-l resistance which, in turn, contributed to his growth failure.
authors.affiliation: St. Christopher's Hospital for Children, 3601 A Street, Philadelphia, Pennsylvania 19134, USA.
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
authors.forename: Marie J
authors.initials: MJ
authors.lastname: Walenkamp
authors.forename: Arjan
authors.initials: A
authors.lastname: Lankester
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.forename: Francesco
authors.initials: F
authors.lastname: De Luca
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006130:Growth Disorders / Q000235:genetics* / Q000378:metabolism; D019382:Human Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009154:Mutation / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; C000606204:NFKBIA protein, human; C491923:PHLDA1 protein, human; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D019382:Human Growth Hormone; D000072000:NF-KappaB Inhibitor alpha; D007334:Insulin-Like Growth Factor I