Identification of an androgen response element in intron 8 of the sterol regulatory element-binding protein cleavage-activating protein gene allowing direct regulation by the androgen receptor.
Sterol regulatory element-binding proteins (SREBPs) are transcription regulators that play a pivotal role in intracellular lipid homeostasis. They are synthesized as inactive precursor proteins in the endoplasmic reticulum, where they are retained by SREBP cleavage-activating protein (SCAP), a sterol sensing protein that in turn is linked to a retention protein complex. Low intracellular sterol concentrations weaken the interaction of SCAP with its retention proteins and allow translocation of the SREBP.SCAP complex to the Golgi compartment where SREBP is proteolytically cleaved and activated. Previous studies on the mechanisms by which androgens provoke a coordinated activation of lipogenic pathways in prostate cancer cells have suggested an alternative pathway of activation in which androgens increase the expression of SCAP and favor translocation of the SREBP.SCAP complex to the Golgi apparatus by disturbing the balance between SCAP and its retention proteins. Here we show that the SCAP gene contains an androgen-responsive region located in intron 8. This region interacts directly with the androgen receptor and confers androgen responsiveness to promoter-reporter constructs transfected in LNCaP cells. It contains a noncanonical androgen response element GGAAGAaaaTGTACC that interacts not only with the androgen receptor but also with the glucocorticoid receptor and that also confers glucocorticoid responsiveness. The identification of a steroid response element in intron 8 of the SCAP gene further supports the contention that SCAP is a direct target for steroid hormone action.
Heemers
Hannelore
H
Laboratory for Experimental Medicine and Endocrinology, Faculty of Medicine, Onderwijs en Navorsing, Gasthuisberg, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Verrijdt
Guy
G
Organe
Sophie
S
Claessens
Frank
F
Heyns
Walter
W
Verhoeven
Guido
G
Swinnen
Johannes V
JV
D020816:Amino Acid Motifs; D000728:Androgens / Q000378:metabolism*; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007438:Introns; D007700:Kinetics; D050356:Lipid Metabolism; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection
D000728:Androgens; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D011965:Receptors, Glucocorticoid; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases