RNA Polymerase II Elongation Control

Peng, Jiexin; Liu, M.; Marion, Jon E.; Zhu, Yizhi; Price, David H.

doi:10.1101/sqb.1998.63.365

Cited by 35 publications

(30 citation statements)

References 47 publications

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“…We found that ARC employs an indirect mechanism to inhibit transcription, similar to DRB and flavopiridol (4,32). Phosphorylation of the CTD of RNA polymerase II by P-TEFb kinase is a requisite step for transcriptional elongation (33,34), and ARC blocks this process as seen by its inhibition of P-TEFb, leading to decreased phosphorylation on RNA polymerase II (Fig. 2C and D).…”

Section: Discussionmentioning

confidence: 94%

A Novel Transcriptional Inhibitor Induces Apoptosis in Tumor Cells and Exhibits Antiangiogenic Activity

Radhakrishnan

Gartel

2006

Cancer Research

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Using a high-throughput cell-based assay, we identified a nucleoside analogue 4-amino-6-hydrazino-7-B-D-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide (ARC), which has the properties of a general transcriptional inhibitor. Specifically, ARC inhibits the phosphorylation of RNA polymerase II by positive transcription elongation factor-b, leading to a block in transcriptional elongation. ARC was able to potently repress p53 targets p21 and hdm2 (human homologue of mdm2) protein levels, but dramatically increased p53 levels similar to other transcriptional inhibitors, including flavopiridol. This increase in p53 corresponded to the down-regulation of shortlived protein hdm2, which is a well-established negative regulator of p53. Remarkably, ARC induced potent apoptosis in human tumor and transformed, but not in normal cells, and possessed strong antiangiogenic activity in vitro. Although ARC promoted the accumulation of p53, ARC-induced apoptosis in tumor cells was p53-independent, suggesting that it may be useful for the treatment of tumors with functionally inactive p53. Furthermore, cell death induced by ARC had a strong correlation with down-regulation of the antiapoptotic gene survivin, which is often overexpressed in human tumors. Taken together, our data suggests that ARC may be an attractive candidate for anticancer drug development. (Cancer Res 2006; 66(6): 3264-70)

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Section: Discussionmentioning

confidence: 94%

A Novel Transcriptional Inhibitor Induces Apoptosis in Tumor Cells and Exhibits Antiangiogenic Activity

Radhakrishnan

Gartel

2006

Cancer Research

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“…To determine if flavopiridol directly inhibited RNA polymerase II, early elongation complexes were isolated under stringent washing conditions that eliminate all known factors able to affect the elongation properties of the polymerase (17). The polymerases in these complexes are able to efficiently, albeit slowly, elongate their nascent transcripts as indicated by the 1-, 2-, 3-, 4-, and 5-min chase time points (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Transcription and Kinase Assays-Pulse-chase transcription assays were carried out as described previously (16,17) except for modifications indicated in the text. Kinase assays were as described in Marshall et al (18) using Drosophila RNA polymerase II as the substrate.…”

Section: Methodsmentioning

confidence: 99%

Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication

Chao¹,

Fujinaga²,

Marion³

et al. 2000

Journal of Biological Chemistry

440

435

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Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by flavopiridol with a K i of 3 nM. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC 50 of less than 10 nM.

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“…Also, being a nucleoside analog, it is conceivable that ARC may affect a number of kinases. In fact, the basis of transcriptional repression by ARC is tied to its ability to inhibit CDK9 kinase (Radhakrishnan and Gartel, 2006a, b), which plays a central role in transcriptional elongation (Janicke et al, 1998;Peng et al, 1998). Here, we tested if ARC could affect the well-known PI3K/Akt kinase survival pathway, and found that ARC indeed inhibited phosphorylation of Akt as well as its downstream target GSK3.…”

Section: Targeting Akt In Neuroblastoma Cells Sk Radhakrishnan Et Almentioning

confidence: 99%

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

et al. 2007

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We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7-b-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1-b-Dribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARCinduced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.

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RNA Polymerase II Elongation Control

Cited by 35 publications

References 47 publications

A Novel Transcriptional Inhibitor Induces Apoptosis in Tumor Cells and Exhibits Antiangiogenic Activity

A Novel Transcriptional Inhibitor Induces Apoptosis in Tumor Cells and Exhibits Antiangiogenic Activity

Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

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