title: Increased growth hormone receptor (GHR) degradation due to over-expression of cytokine inducible SH2 domain-containing protein (CIS) as a cause of GH transduction defect (GHTD).
abstract: OBJECTIVE
  Children with growth hormone transduction defect (GHTD) have impaired growth and signal transducer and activator of transcription 3 (STAT3) activation. Here, we examine the etiology of GHTD.
  
  
  METHODS
  Control (Cf) and GHTD (Pf) children's fibroblasts were induced with hGH, MG132, lactacystin or silence RNA/CIS (siCIS). Western immunoblotting (WI) examined protein expression. Immunofluorescent microscopy (IF) examined cellular localization.
  
  
  RESULTS
  (i) Pf showed retarded activation of pJAK2 and pSTAT-5 and increased ubiquitinated CIS (UbCIS) by WI. (ii) After MG132, Pf showed normal activation of pJAK2, pSTAT5 and pSTAT3. (iii) IF showed membrane (ML) and cytoplasmic localization (CL) of the GHR in Cf while the Pf showed only CL. In Pf, induction with lactacystin or siCIS changed the localization of the GHR to ML.
  
  
  CONCLUSIONS
  In GHTD, abnormal GH signalling may be caused by over-expression of CIS, which may increase degradation of GHR, thus reducing membrane GHR availability, delaying activation of pJAK2 and pSTAT5 and reducing activation of pSTAT3.
authors: Department of Nursing, University of Peloponnese, Plateon Sparta, Greece. arojas@uop.gr
authors: Andrea Paola Rojas
authors: AP
authors: Gil
authors: Eirini
authors: E
authors: Kostopoulou
authors: Ioulia
authors: I
authors: Karageorgou
authors: Konstantinos
authors: K
authors: Kamzelas
authors: Bessie Eugenia
authors: BE
authors: Spiliotis
mesh_terms: D002478:Cells, Cultured; D002648:Child; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D005260:Female; D006130:Growth Disorders / Q000209:etiology*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011986:Receptors, Somatotropin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D053614:Janus Kinase 2; D046988:Proteasome Endopeptidase Complex; D011986:Receptors, Somatotropin; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; C493956:CDKN1A protein, human; C494086:STAT3 protein, human; C507924:JAK2 protein, human