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Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.

Lu H, Xue Y, Xue Y, Yu GK, Arias C, Lin J, Fong S, Faure M, Weisburd B, Ji X, Mercier A, Sutton J, Luo K, Gao Z, Zhou Q - Elife (2015)

Bottom Line: Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing.While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment.Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.

ABSTRACT
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.

No MeSH data available.


Related in: MedlinePlus

Biphasic response of MYC mRNA production throughout the course of CDK9 inhibition by i-CDK9.DOI:http://dx.doi.org/10.7554/eLife.06535.008
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fig3s1: Biphasic response of MYC mRNA production throughout the course of CDK9 inhibition by i-CDK9.DOI:http://dx.doi.org/10.7554/eLife.06535.008

Mentions: Among the small group of genes that showed at least twofold increase in expression after 8 hr of i-CDK9 treatment, the proto-oncogene MYC has caught our special attention because of its extreme importance in cell growth control and oncogenic transformation and also the fact that its expression has been shown to depend on CDK9 (Kanazawa et al., 2003; Rahl et al., 2010; Huang et al., 2014). Microarray analysis performed at three different time points (2, 8 and 16 hr) indicates that MYC expression in i-CDK9-treated HeLa cells displayed an interesting biphasic responses with a small initial decrease (within 2 hr) followed by a dramatic rebound (around 8 hr and continue at 16 hr) in the presence of continuous CDK9 inhibition by i-CDK9 (Figure 3A). This result was further confirmed by qRT-PCR analysis of MYC mRNA levels in cells treated with i-CDK9 or DMSO (Figure 3—figure supplement 1).10.7554/eLife.06535.007Figure 3.Induction of MYC mRNA production in response to sustained inhibition of CDK9 by i-CDK9 and the requirement of MYC's natural genomic structure in this process.


Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.

Lu H, Xue Y, Xue Y, Yu GK, Arias C, Lin J, Fong S, Faure M, Weisburd B, Ji X, Mercier A, Sutton J, Luo K, Gao Z, Zhou Q - Elife (2015)

Biphasic response of MYC mRNA production throughout the course of CDK9 inhibition by i-CDK9.DOI:http://dx.doi.org/10.7554/eLife.06535.008
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490784&req=5

fig3s1: Biphasic response of MYC mRNA production throughout the course of CDK9 inhibition by i-CDK9.DOI:http://dx.doi.org/10.7554/eLife.06535.008
Mentions: Among the small group of genes that showed at least twofold increase in expression after 8 hr of i-CDK9 treatment, the proto-oncogene MYC has caught our special attention because of its extreme importance in cell growth control and oncogenic transformation and also the fact that its expression has been shown to depend on CDK9 (Kanazawa et al., 2003; Rahl et al., 2010; Huang et al., 2014). Microarray analysis performed at three different time points (2, 8 and 16 hr) indicates that MYC expression in i-CDK9-treated HeLa cells displayed an interesting biphasic responses with a small initial decrease (within 2 hr) followed by a dramatic rebound (around 8 hr and continue at 16 hr) in the presence of continuous CDK9 inhibition by i-CDK9 (Figure 3A). This result was further confirmed by qRT-PCR analysis of MYC mRNA levels in cells treated with i-CDK9 or DMSO (Figure 3—figure supplement 1).10.7554/eLife.06535.007Figure 3.Induction of MYC mRNA production in response to sustained inhibition of CDK9 by i-CDK9 and the requirement of MYC's natural genomic structure in this process.

Bottom Line: Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing.While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment.Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.

ABSTRACT
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.

No MeSH data available.


Related in: MedlinePlus