Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila.
Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila.
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DOI：
10.1242/dmm.049650
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发表时间：
2022-11-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
脂肪生成基因表达的微调对于维持细胞内脂质的长期内稳态非常重要。转录因子SREBP家族是控制脂肪生成和胆固醇生成基因转录的主要调节因子，但调节SREBP依赖性转录的机制仍未完全清楚。我们之前报道过，转录辅因子中介体复合物的一个亚基CDK8在一个保守的苏氨酸残基上使SREBP磷酸化。在此，我们以果蝇为模型系统进行观察，发现磷酸化缺陷型SREBP蛋白（SREBP - Thr390Ala）比野生型SREBP更稳定，在体内刺激脂肪生成基因的表达和促进脂肪生成方面更有效。此外，饥饿会阻断野生型SREBP诱导的脂肪生成基因转录的作用，而磷酸化缺陷型SREBP对这种作用具有抗性。而且，我们的生化分析确定了SREBP的N端无序区域中的六个高度保守的氨基酸残基，这些残基是其与Cdk8和小中介体复合物的MED15亚基相互作用所必需的。这些结果支持Cdk8和MED15的协同作用对于严格调节SREBP依赖性转录至关重要。
总结：Cdk8和MED15的协同作用在严格调节果蝇细胞核中SREBP依赖性转录和从头脂肪生成方面起着关键作用。
Fine-tuning of lipogenic gene expression is important for the maintenance of long-term homeostasis of intracellular lipids. The SREBP family of transcription factors are master regulators that control the transcription of lipogenic and cholesterogenic genes, but the mechanisms modulating SREBP-dependent transcription are still not fully understood. We previously reported that CDK8, a subunit of the transcription co-factor Mediator complex, phosphorylates SREBP at a conserved threonine residue. Here, using Drosophila as a model system, we observed that the phosphodeficient SREBP proteins (SREBP-Thr390Ala) were more stable and more potent in stimulating the expression of lipogenic genes and promoting lipogenesis in vivo than wild-type SREBP. In addition, starvation blocked the effects of wild-type SREBP-induced lipogenic gene transcription, whereas phosphodeficient SREBP was resistant to this effect. Furthermore, our biochemical analyses identified six highly conserved amino acid residues in the N-terminus disordered region of SREBP that are required for its interactions with both Cdk8 and the MED15 subunit of the small Mediator complex. These results support that the concerted actions of Cdk8 and MED15 are essential for the tight regulation of SREBP-dependent transcription. Summary: The concerted actions of Cdk8 and MED15 play critical roles in tight regulation of SREBP-dependent transcription in the nucleus and de novo lipogenesis in Drosophila.
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DOI：
10.1016/j.bbrc.2014.05.046
发表时间：
2014-07-11
影响因子：
3.1
作者：
Dong Q;Giorgianni F;Deng X;Beranova-Giorgianni S;Bridges D;Park EA;Raghow R;Elam MB
通讯作者：
Elam MB
影响因子：
4
作者：
Dong Q;Giorgianni F;Beranova-Giorgianni S;Deng X;O'Meally RN;Bridges D;Park EA;Cole RN;Elam MB;Raghow R
通讯作者：
Raghow R
DOI：
10.1186/s40880-018-0301-4
发表时间：
2018-05-21
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Cheng C;Geng F;Cheng X;Guo D
通讯作者：
Guo D
DOI：
10.1073/pnas.0407024101
发表时间：
2004-10-26
影响因子：
11.1
作者：
Dirks, RM;Pierce, NA
通讯作者：
Pierce, NA
影响因子：
4.3
作者：
Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.