Sterol regulatory element-binding protein 1 is negatively modulated by PKA phosphorylation
Sterol regulatory element-binding protein 1 is negatively modulated by PKA phosphorylation
复制标题
DOI：
10.1152/ajpcell.00374.2005
复制
发表时间：
2006-06-01
影响因子：
5.5
通讯作者：
Shyy, JYJ
中科院分区：
文献类型：
--
作者：
Lu, M;Shyy, JYJ
固醇调节元件结合蛋白（SREBP）-1a和-1c是调节细胞脂质生物合成的关键转录因子。我们在体外和HepG2细胞中鉴定了位于SREBP-1a的NH 2末端的Ser338是PKA磷酸化位点。PKA磷酸化这个网站衰减DNA占用，染色质免疫沉淀试验，以及随后的反式激活。相反，用Ala [SREBP-1a（N）-S338A]取代Ser增加了反式激活。尽管它与野生型SREBP-1a（N）或S338A形成异二聚体，但与其自身不形成同源二聚体，SREBP-1a（N）-S338D（用Asp取代Ser）降低DNA结合。SREBP-1c的Ser314（SREBP-1a Ser338的对应物）也被PKA磷酸化。因此，腺病毒介导的SREBP1c（N）-S314D在HepG2细胞中的表达延迟了脂肪生成。我们的研究结果表明，cAMP-PKA途径，通过磷酸化SREBP-1，可以调节肝细胞系的脂质代谢。
Sterol regulatory element-binding protein (SREBP)-1a and -1c are key transcription factors that regulate lipid biosynthesis in cells. We identified that Ser338 located at the NH2 terminus of SREBP-1a is a PKA phosphorylation site in vitro and in HepG2 cells. PKA phosphorylation of this site attenuated DNA occupancy, as revealed by chromatin immunoprecipitation assay, and the ensuing transactivation. In contrast, replacing Ser with Ala [SREBP-1a(N)-S338A] increased transactivation. Although it forms heterodimers with the wild-type SREBP-1a(N) or S338A but not a homodimer with itself, SREBP-1a(N)-S338D (replacing Ser with Asp) decreased DNA binding. Ser314 of SREBP-1c, the counterpart of SREBP-1a Ser338, was also phosphorylated by PKA. Accordingly, the adenovirus-mediated expression of SREBP1c(N)-S314D in HepG2 cells retarded lipogenesis. Our results indicate that the cAMP-PKA pathway, by phosphorylating SREBP-1, may modulate lipid metabolism in liver cell lines.