Figure 1

GnRH-I and GnRH-II signaling in human gynecological cancer cells: A) GnRH-I activates a phosphotyrosine phosphatase (PTP) inhibiting the mitogenic signal transduction of growth factor receptors resulting in downregulation of cell proliferation. B) GnRH-I downregulates epidermal growth factor (EGF) receptor mRNA expression. C) Activated GnRH-I receptor induces nucleus factor κB (NFκB) activation and nuclear translocation of activated NFκB. Activated NFκB now couples to κB DNA binding sites and induces expression of anti-apoptotic mechanisms. D) GnRH-I activates c-Jun N-terminal kinase (JNK), induces JunD-DNA binding and stimulates activator protein (AP-1) activity, resulting in reduced proliferation as indicated by increased G_0/1 phase of cell cycle and decreased DNA synthesis. E) Unknown signal transduction of a putative human GnRH-II receptor. In human gynecological cancer cells GnRH-I analogs mediate antiproliferative actions via inhibition of growth factor-induced mitogenic signal transduction. In addition GnRH-I induces growth factor receptor downregulation. GnRH-I protects the cancer cells from apoptosis via activation of NFκB, stimulates AP-1 activity and extends cell cycle. PPTK, receptor protein tyrosine kinase; GRB₂, adaptor protein; SOS, guanine nucleotide exchange factor; RAS, small GTPase; RAF, a protein-serine/threonine kinase; MAPK-K, mitogen activated kinase kinase; MAPK, mitogen activated kinase; TCF, transcription factor; IκB, inhibitory κB; Gq, G-protein αq; Gi, G-protein αi; p50, p65, NFκB subunits.