Foulkes N S, Laoide B M, Schlotter F, Sassone-Corsi P
Laboratoire de Génétique Moléculaire des Eucaryotes du Centre National de la Recherche Scientifique, Unité 184, de la Santé et de la Recherche Médicale, Faculté de Médecine, Strasbourg, France.
Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5448-52. doi: 10.1073/pnas.88.12.5448.
Protooncogene c-fos is induced by activation of adenylate cyclase through the major cAMP-responsive element (CRE) centered at position -60 of the promoter. cAMP induction is followed by a rapid decrease in transcriptional rate, reminiscent of down-regulation after serum stimulation. Fos protein is known to negatively autoregulate serum-induced transcription of c-fos promoter, but whether Fos is responsible for down-regulation of cAMP-induced transcription is unclear. Here we show that Fos is unable to down-regulate CRE-mediated activation. We present evidence that the transcriptional antagonist CRE modulator (CREM) can bind to c-fos CRE and heterodimerize with activator CRE-binding protein, thereby blocking cAMP induction. Furthermore, expression of antisense CREM enhances c-fos basal and cAMP-induced transcription. CREM does not antagonize serum-induced transcription; therefore, we conclude that down-regulation of c-fos is exerted by different effectors, depending upon which signal transduction pathway is activated. We speculate that, by its c-fos down-regulatory function, CREM may act as an antioncogene.
原癌基因c-fos是通过腺苷酸环化酶的激活，经启动子-60位的主要cAMP反应元件（CRE）诱导产生的。cAMP诱导后转录速率迅速下降，这与血清刺激后的下调相似。已知Fos蛋白可负向自动调节血清诱导的c-fos启动子转录，但Fos是否负责cAMP诱导转录的下调尚不清楚。在此我们表明Fos无法下调CRE介导的激活。我们提供的证据表明，转录拮抗剂CRE调节因子（CREM）可与c-fos CRE结合，并与激活剂CRE结合蛋白形成异二聚体，从而阻断cAMP诱导。此外，反义CREM的表达增强了c-fos基础转录和cAMP诱导的转录。CREM并不拮抗血清诱导的转录；因此，我们得出结论，c-fos的下调是由不同的效应器介导的，这取决于激活的是哪种信号转导途径。我们推测，通过其对c-fos的下调功能，CREM可能作为一种抗癌基因发挥作用。
