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

Abstract

SREBPs are synthesized as 125-kDa inactive precursor proteins, and immediately upon their synthesis they are inserted into the membranes of the endoplasmic reticulum where they form tight complexes with an escort protein known as the SREBP cleavage-activating protein (SCAP). SCAP plays a pivotal role in the control of SREBP signaling. In fact, SCAP does not only bind SREBP but, through its amino-terminal sterolsensing domain, it also interacts with a retention protein complex consisting of at least two endoplasmic reticulum proteins (designated insulin-induced gene 1 and 2; Insig 1 and 2) that serve to retain the SREBP⅐SCAP complex into the membranes of the endoplasmic reticulum. In the "classical" SREBP activation pathway, a decrease in the intracellular concentration of sterols changes the conformation of the sterol-sensing part of SCAP, weakens its interaction with the retention proteins, and allows translocation of the SREBP⅐SCAP complex to the Golgi apparatus where SREBP is proteolytically cleaved and activated. The active 68-kDa SREBP fragment migrates to the nucleus where it increases the transcription of a large set of sterol-responsive element (SRE) containing genes encoding lipogenic enzymes belonging to the pathways of fatty acid and cholesterol synthesis (1-7).Our studies on the mechanisms by which androgens provoke a coordinated activation of lipogenic pathways in androgenresponsive prostate tumor lines have suggested an alternative pathway of SREBP activation in which androgens change the expression rather than the conformation of SCAP (8,9). In this pathway, increased expression of SCAP shifts the balance between SCAP and its retention proteins and favors translocation of the SREBP⅐SCAP complex to the Golgi apparatus. Evidence for the existence of this pathway was derived from several observations (9). 1) In two independent prostate tumor lines (LNCaP and MDA-PCa-2a) androgens cause major changes in the expression of SCAP both at the mRNA and at the protein level, whereas no or only minor changes were observed for other critical components of the SREBP pathway (the SREBP precursor proteins SREBP-1a, -1c, and -2; the site 1 and site 2 proteases responsible for SREBP cleavage).2) The observed increase in SCAP expression was shown to be a cause rather than a consequence of SREBP activation. Induction of SCAP expression coincided with nuclear translocation of SREBP but

Ginsenoside F2 Reduces Hair Loss by Controlling Apoptosis through the Sterol Regulatory Element-Binding Protein Cleavage Activating Protein and Transforming Growth Factor-β Pathways in a Dihydrotestosterone-Induced Mouse Model

“…21) If the expression of SCAP was increased by bind of DHT to the AR, ER stress would be induced causing the Golgi apparatus to bind to SREBP.…”

Sterol Regulatory Element–Binding Protein-1c Represses the Transactivation of Androgen Receptor and Androgen-Dependent Growth of Prostatic Cells

“…Precursor SREBP-1c, which is bound in the endoplasmic reticulum, is expressed in prostate cancer cells, and long-term (2 days) exposure of androgens stimulates the production of mature SREBPs (active form of SREBPs) and enhances lipogenic gene expression (34)(35)(36). To investigate the effect of SREBP-1c on AR signaling in the nucleus, we did reporter assays in LNCaP cells, AR-positive cancer cells, using ARresponsive ARE 2 -TATA-luc that contains two copies of the ARbinding element.…”

“…AR directly binds to ARE within the intron of the SCAP gene, and increases both the mRNA and protein levels of SREBP cleavage-activating protein (35,36). In addition, long-term (2 days) androgen treatment of prostate cancer cells enhances the production of mature SREBPs in the nucleus, resulting in the induction of lipogenic gene expression (34,36).…”

Effect of Daxx on cholesterol accumulation in hepatic cells

“…The active 68-kDa SREBP fragment migrates to the nucleus and increases the transcription of sterol-responsive element (SRE) that contains many genes encoding lipogenic enzymes belonging to the pathways of cholesterol synthesis [26] . Daxx can inhibit AR transcriptional activity [6,7] , which can down-regulates the activity of SCAP [9] . Thus, we checked the activity of SREBP-1 and detected that Daxx has the potential to decrease the expression of active SREBP-1.…”

“…Androgens affect lipogenic gene expression not only in tumor cells, but also in normal androgen target tissues in vivo [8] . AR can directly upregulate sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) by binding an androgen response element in intron 8 of the SCAP gene [9] . Activated SREBP can increase the mRNA and protein levels of genes involved in fatty acid (fatty acid synthase and acetylCoA-carboxylase), and cholesterol synthesis (HMG-CoAreductase and farnesyl diphosphate synthase) [10] .…”