title: Somatostatin modulates G-CSF-induced but not interleukin-3-induced proliferative responses in myeloid 32D cells via activation of somatostatin receptor subtype 2.
abstract: BACKGROUND
  Somatostatin, originally identified as a peptide involved in neurotransmission, functions as an inhibitor of multiple cellular responses, including hormonal secretion and proliferation. Somatostatin acts through activation of G-protein-coupled receptors of which five subtypes have been identified. We have recently established that human CD34/c-kit expressing hematopoietic progenitors and acute myeloid leukemia (AML) cells exclusively express SSTR2. A major mechanism implicated in the antiproliferative action of somatostatin involves activation of the SH2 domain-containing protein tyrosine phosphatase SHP-1. While 0.1-1 x 10(-9) M of somatostatin, or its synthetic stable analog octreotide, can inhibit G-CSF-induced proliferation of AML cells, little or no effects are seen on GM-CSF- or IL-3-induced responses.
  
  
  METHODS
  To study the mechanisms underlying the antiproliferative responses of myeloblasts to somatostatin, clones of the IL-3-dependent murine cell line 32D that stably express SSTR2 and G-CSF receptors were generated.
  
  
  RESULTS
  Similar to AML cells, octreotide inhibited G-CSF-induced but not IL-3-induced proliferative responses of 32D[G-CSF-R/SSTR2] cells. Somatostatin induced SHP-1 activity and inhibited G-CSF-induced, but not IL-3-induced, activation of the signal transducer and activator of transcription proteins STAT3 and STAT5.
  
  
  CONCLUSIONS
  Based on these data and previous results, we propose a model in which recruitment and activation of the tyrosine phosphatase SHP-1 by SSTR2 is involved in the selective negative action of somatostatin on G-CSF-R signaling.
authors.affiliation: Institute of Hematology, Erasmus University Rotterdam, Rotterdam, The Netherlands.
authors.forename: S P
authors.initials: SP
authors.lastname: Oomen
authors.forename: A C
authors.initials: AC
authors.lastname: Ward
authors.forename: L J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: S W
authors.initials: SW
authors.lastname: Lamberts
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
authors.forename: I P
authors.initials: IP
authors.lastname: Touw
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D016179:Granulocyte Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D051379:Mice; D008894:Milk Proteins; D015282:Octreotide / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000494:pharmacology* / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006728:Hormones; D007377:Interleukin-3; D008894:Milk Proteins; D017481:Receptors, Somatostatin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor; D013004:Somatostatin; C093733:somatostatin receptor 2; D015282:Octreotide