Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol

Lam, Lloyd T.; Pickeral, Oxana K.; Peng, A; Rosenwald, Andreas; Hurt, Elaine M.; Giltnane, Jena M.; Averett, Lauren; Zhao, Hong; Davis, R. Eric; Sathyamoorthy, Mohan; Wahl, Larry M.; Harris, Eric D; Mikovits, Judy A.; Monks, Anne; Hollingshead, Melinda G.; Sausville, Edward A.; Staudt, Louis M.

doi:10.1186/gb-2001-2-10-research0041

Cited by 301 publications

(91 citation statements)

References 42 publications

(51 reference statements)

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“…On the other hand, these anti-apoptotic proteins are dependent on continuous RNAPII activity mediated by overexpression of CDK9. CDK9 inhibition using small-molecule inhibitors (Table 3) downregulates these short-lived anti-apoptotic proteins and triggers cell death (Lam et al 2001, Chen et al 2009). In 2014, Booher et al showed that CDK9 inhibitor dinaciclib induces apoptosis by downregulating MCL-1 and BCL-XL in 22rv1 and PC3 PCa cells, as well as other 11 solid tumor cells.…”

Section: Targeting Cdk9 In Crpcmentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and antiapoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.

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Section: Targeting Cdk9 In Crpcmentioning

confidence: 99%

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Rahaman

Kumarasiri

Mekonnen

et al. 2016

Endocrine-Related Cancer

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“…10-15). However, there has been only limited application of DNA microarrays to the study of kinetic events such as mRNA decay (16)(17)(18).…”

mentioning

confidence: 99%

Global analysis of mRNA decay and abundance in Escherichia coli at single-gene resolution using two-color fluorescent DNA microarrays

Bernstein

Khodursky

Lin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

766

711

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Much of the information available about factors that affect mRNA decay in Escherichia coli, and by inference in other bacteria, has been gleaned from study of less than 25 of the Ϸ4,300 predicted E. coli messages. To investigate these factors more broadly, we examined the half-lives and steady-state abundance of known and predicted E. coli mRNAs at single-gene resolution by using two-color fluorescent DNA microarrays. An rRNA-based strategy for normalization of microarray data was developed to permit quantitation of mRNA decay after transcriptional arrest by rifampicin. We found that globally, mRNA half-lives were similar in nutrient-rich media and defined media in which the generation time was approximately tripled. A wide range of stabilities was observed for individual mRNAs of E. coli, although Ϸ80% of all mRNAs had half-lives between 3 and 8 min. Genes having biologically related metabolic functions were commonly observed to have similar stabilities. Whereas the half-lives of a limited number of mRNAs correlated positively with their abundance, we found that overall, increased mRNA stability is not predictive of increased abundance. Neither the density of putative sites of cleavage by RNase E, which is believed to initiate mRNA decay in E. coli, nor the free energy of folding of 5 or 3 untranslated region sequences was predictive of mRNA half-life. Our results identify previously unsuspected features of mRNA decay at a global level and also indicate that generalizations about decay derived from the study of individual gene transcripts may have limited applicability.RNA degradation ͉ RNA half-life ͉ transcript abundance T he rate of mRNA degradation plays a central role in the metabolism of nucleic acids in both prokaryotic and eukaryotic cells (for reviews see refs. 1-5). mRNA decay has been studied in a range of organisms, and much has been learned about the substrate features and ribonucleolytic enzymes that influence mRNA stability. In the case of Escherichia coli, experimenters have demonstrated that extensive variation exists in the rate of decay of individual mRNAs and that specific features of the mRNA sequence as well as transcript secondary structure can be important determinants of such variation (1, 3). Additionally, although the half-lives of some RNAs depend on the physiological state of the cell, as influenced by genetic and environmental factors, the half-lives of other RNAs seem to be independent of cell physiology (6, 7).Much of the information available about RNA decay has been derived from study of RNAs encoded by a very limited number of genes. In fact, we can find published reports of RNA half-life for less than 25 of the 4,288 predicted ORFs in the E. coli genome. Current models of mRNA decay are based on this relatively limited experimental sampling of message turnover. To gain a broader understanding of the fate of mRNAs in E. coli we adapted DNA microarray methodology to measure the decay of each chromosomally encoded mRNA simultaneously.DNA microarrays containing sequences derived ...

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“…5 shows that both cellular protein and mRNA levels of Mcl-1, XIAP, and survivin are down-regulated by ibulocydine in a time-dependent manner in HCC cells. It has been suggested that prolonged inhibition of Cdk7 and Cdk9 within cells induces apoptosis (35). The prolonged inhibition of Cdk7 and Cdk9 eventually affected all transcripts produced by RNA polymerase II, and subsequently their proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The prolonged inhibition of Cdk7 and Cdk9 eventually affected all transcripts produced by RNA polymerase II, and subsequently their proteins. This has an immediate effect upon transcripts and proteins with inherently rapid turnover rates (35), such as Mcl-1, XIAP, survivin, etc. Thus, studies have speculated that prolonged Cdk7/9-mediated inhibition of transcription decreases Mcl-1, XIAP, and survivin expression, releasing their ability to block primed cells from undergoing apoptosis (36).…”

Section: Discussionmentioning

confidence: 99%

Ibulocydine Is a Novel Prodrug Cdk Inhibitor That Effectively Induces Apoptosis in Hepatocellular Carcinoma Cells

Cho

Kim

Surh³

et al. 2011

Journal of Biological Chemistry

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Hepatocellular carcinoma (HCC)3 is a leading cause of mortality in patients with liver cirrhosis (1). In the United States, the incidence of HCC has risen during the last few decades from 1.3/100,000 population between 1978 and 1980 to 3.3/100,000 population between 1998 and 2001 (2, 3). This is likely to continue, primarily due to progressive liver diseases attributable to the hepatitis C virus in individuals infected a few decades ago (4). However, as hepatitis B virus infection is more prevalent globally than hepatitis C virus, hepatitis B virus remains the single most important cause of HCC worldwide, and is particularly high in Asia and Africa (5). Treatment of HCC is clinically difficult, as HCC expresses multidrug-resistance genes and is insensitive to current chemotherapeutic agents (6). HCC cells are characterized by high cellular levels of cyclin-dependent kinases (Cdks). Up-regulation of Cdks results from the inactivation of p16 Ink4, p21Waf1 and p27 Kip1 , Cdk inhibitory proteins, and abnormal activation of cyclins (7-10). For this reason, Cdk inhibitors are strong candidates for the treatment of HCC, and some (e.g. olomoucine, roscovitine and flavopiridol) have been tested in clinical trials (11).Cdks regulate two biological processes essential for cancer cell survival: cell cycle progression and gene transcription (12). They control entry into each stage of the cell cycle by phosphorylating key substrates such as pRb (13,14). Cdks usually form heterodimers with cyclins to create active complexes and, because cyclin levels oscillate throughout the cell cycle, this contributes to the temporal activation of specific Cdks. Cdks also regulate transcription by phosphorylating the carboxylterminal domain (CTD) of the large subunit of RNA polymerase II (15). In humans, the CTD contains 52 heptapeptide (YSPTSPS) repeats that can be phosphorylated on serines, threonines, and tyrosines (15). A number of Cdks phosphorylate these sites, including Cdk7/cyclin H/Mat1 (part of the TFIIH complex that initiates transcription) (16) and Cdk9/cyclin T (also called P-TEFb), which activates transcriptional elongation (17-21).Mcl-1, an anti-apoptotic member of the Bcl-2 family (22), was first identified as a protein up-regulated in a human carcinoma cell line induced to differentiate along the monocyte lineage (23), and is essential for the survival of carcinoma cells (24 -27). Mcl-1 is thought to act by antagonizing pro-apoptotic proteins such as Bim (28). Inhibitor of apoptosis protein (IAP) is a family of proteins that regulates cell death; X-linked IAP (XIAP) and survivin are two important members of this family in mammals. Both inhibit caspases and block apoptosis (29).Ibulocydine, ((2S,3S,4S,5S)-5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo [2,3-d]pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate, is an isobutyrate ester prodrug of a novel synthetic Cdk inhibitor, BMK-Y101 (4-amino-6-bromo-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-pyrrolo[2,3-d]pyrimidine-5-carboxamide) ...

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Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol

Abstract: Background: Flavopiridol, a flavonoid currently in cancer clinical trials, inhibits cyclin-dependent kinases (CDKs) by competitively blocking their ATP-binding pocket. However, the mechanism of action of flavopiridol as an anti-cancer agent has not been fully elucidated.

Cited by 301 publications

References 42 publications

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Targeting CDK9: a promising therapeutic opportunity in prostate cancer

Global analysis of mRNA decay and abundance in Escherichia coli at single-gene resolution using two-color fluorescent DNA microarrays

Ibulocydine Is a Novel Prodrug Cdk Inhibitor That Effectively Induces Apoptosis in Hepatocellular Carcinoma Cells

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