Multiple mechanisms of growth hormone-regulated gene transcription.
Diverse physiological actions of growth hormone (GH) are mediated by changes in gene transcription. Transcription can be regulated at several levels, including post-translational modification of transcription factors, and formation of multiprotein complexes involving transcription factors, co-regulators and additional nuclear proteins; these serve as targets for regulation by hormones and signaling pathways. Evidence that GH regulates transcription at multiple levels is exemplified by analysis of the proto-oncogene c-fos. Among the GH-regulated transcription factors on c-fos, C/EBPbeta appears to be key, since depletion of C/EBPbeta by RNA interference blocks the stimulation of c-fos by GH. The phosphorylation state of C/EBPbeta and its ability to activate transcription are regulated by GH through MAPK and PI3K/Akt-mediated signaling cascades. The acetylation of C/EBPbeta also contributes to its ability to activate c-fos transcription. These and other post-translational modifications of C/EBPbeta appear to be integrated for regulation of transcription by GH. The formation of nuclear proteins into complexes associated with DNA-bound transcription factors is also regulated by GH. Both C/EBPbeta and the co-activator p300 are recruited to c-fos in response to GH, altering c-fos promoter activation. In addition, GH rapidly induces spatio-temporal re-localization of C/EBPbeta within the nucleus. Thus, GH-regulated gene transcription mediated by C/EBPbeta reflects the integration of diverse mechanisms including post-translational modifications, modulation of protein complexes associated with DNA and re-localization of gene regulatory proteins. Similar integration involving other transcription factors, including Stats, appears to be a feature of regulation by GH of other gene targets.
Ceseña
Teresa I
TI
Cellular and Molecular Biology Program, University Michigan, Ann Arbor, MI 48109, USA.
Cui
Tracy Xiao
TX
Piwien-Pilipuk
Graciela
G
Kaplani
Julianne
J
Calinescu
Anda-Alexandra
AA
Huo
Jeffrey S
JS
Iñiguez-Lluhí
Jorge A
JA
Kwok
Roland
R
Schwartz
Jessica
J
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D016762:Genes, fos; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D009698:Nucleoproteins / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D022782:CCAAT-Enhancer-Binding Protein-beta; C000715470:MAS1 protein, human; D009698:Nucleoproteins; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D013006:Growth Hormone