title: Autocrine human growth hormone inhibits placental transforming growth factor-beta gene transcription to prevent apoptosis and allow cell cycle progression of human mammary carcinoma cells.
abstract: Multiple cellular effects of human growth hormone (hGH) are mediated by an indirect mechanism requiring transcriptional activation of genes encoding protein effector molecules such as insulin-like growth factor-1. Such protein effector molecules then act directly to mediate the cellular functions of hGH. We report here that autocrine hGH production by mammary carcinoma cells specifically results in the transcriptional repression of the p53-regulated placental transforming growth factor-beta (PTGF-beta) gene. Transcriptional repression of the PTGF-beta gene does not require the p53-binding sites in the PTGF-beta promoter, and autocrine hGH also desensitized the response of the PTGF-beta promoter to p53 overexpression. Transcriptional repression of the PTGF-beta gene is accompanied by consequent decreases in its protein product, Smad-mediated transcription, and its cellular effects that include cell cycle arrest and apoptosis. PTGF-beta specifically inhibited the autocrine hGH-stimulated expression of cyclin D1 required for autocrine hGH-stimulated mammary carcinoma cell cycle progression. Thus, one mechanism by which autocrine hGH promotes an increase in mammary carcinoma cell number is by transcriptional repression of protein effector molecules that promote cell cycle arrest and apoptosis. Such transcriptional repression of negative regulatory factors, such as PTGF-beta, may also be requisite for direct stimulation of mammary carcinoma cell mitogenesis by hGH.
authors: Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Republic of Singapore.
authors: Ralph
authors: R
authors: Graichen
authors: DongXu
authors: D
authors: Liu
authors: Yi
authors: Y
authors: Sun
authors: Kok-Onn
authors: KO
authors: Lee
authors: Peter E
authors: PE
authors: Lobie
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D017930:Genes, Reporter; D006133:Growth Substances / Q000235:genetics*; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010957:Plasmids; D011257:Pregnancy Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D006133:Growth Substances; D016376:Oligonucleotides, Antisense; D011257:Pregnancy Proteins; D016159:Tumor Suppressor Protein p53; D019382:Human Growth Hormone; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D008156:Luciferases