雷公藤是一個有著悠久,、廣泛應用歷史的中藥,。雷公藤甲素(Triptolide, TPL)是雷公藤的主要活性成分之一。近年來大量體內和體外的研究證明,，Triptolide對多種癌癥如白血病,、乳腺癌、胰腺癌及肺癌等均有良好的抗腫瘤活性,。最近的研究發(fā)現(xiàn),，TPL除了特異地影響某些蛋白和信號通路以外，還會抑制廣泛的基因轉錄,，但其作用機理有待進一步明確,。
中科院上海藥物研究所俞強課題組對Triptolide抑制廣泛基因轉錄的分子機制進行了深入研究。研究發(fā)現(xiàn),，Triptolide通過促進RNA聚合酶II中最大及最主要的功能亞基Rpb1磷酸化,，以及隨后的Rpb1的泛素化降解,，從而抑制基因的轉錄。Rpb1上游激酶PTEF-b在Triptolide誘導的Rpb1的磷酸化的過程中發(fā)揮著正調控作用,。研究還發(fā)現(xiàn),，Triptolide可以誘導DNA損傷。這些研究提示,，Triptolide通過造成細胞的DNA損傷,，從而激活P-TEFb，使其磷酸化Rpb1,，造成Rpb1的降解,，從而抑制了廣譜的基因轉錄。
Triptolide是一個具有多種生物活性的化合物,，闡明它的分子作用機制對于其和雷公藤今后在臨床上合理的使用具有重要的指導意義,。該研究于9月13日在線發(fā)表于PLOS ONE上。
研究工作得到了國家自然科學基金委,，國家科技部,，國家重大科技專項和上海市科委的資助。(生物谷Bioon.com)
doi:10.1371/journal.pone.0024407
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Triptolide (TPL) Inhibits Global Transcription by Inducing Proteasome-Dependent Degradation of RNA Polymerase II (Pol II)
Ying Wang1, Jin-jian Lu1,2, Li He1, Qiang Yu1*
Triptolide (TPL), a key biologically active component of the Chinese medicinal herb Tripterygium wilfordii Hook. f., has potent anti-inflammation and anti-cancer activities. Its anti-proliferative and pro-apoptotic effects have been reported to be related to the inhibition of Nuclear Factor κB (NF-κB) and Nuclear Factor of Activated T-cells (NFAT) mediated transcription and suppression of HSP70 expression. The direct targets and precise mechanisms that are responsible for the gene expression inhibition, however, remain unknown. Here, we report that TPL inhibits global gene transcription by inducing proteasome-dependent degradation of the largest subunit of RNA polymerase II (Rpb1) in cancer cells. In the presence of proteosome inhibitor MG132, TPL treatment causes hyperphosphorylation of Rpb1 by activation of upstream protein kinases such as Positive Transcription Elongation Factor b (P-TEFb) in a time and dose dependent manner. Also, we observe that short time incubation of TPL with cancer cells induces DNA damage. In conclusion, we propose a new mechanism of how TPL works in killing cancer. TPL inhibits global transcription in cancer cells by induction of phosphorylation and subsequent proteasome-dependent degradation of Rpb1 resulting in global gene transcription, which may explain the high potency of TPL in killing cancer.
