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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

i-CDK9 (0.3 μM) induces disruption of 7SK snRNP at a time point much earlier than that required to cause about 50% reduction in global pSer2.DOI:http://dx.doi.org/10.7554/eLife.06535.011
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fig4s1: i-CDK9 (0.3 μM) induces disruption of 7SK snRNP at a time point much earlier than that required to cause about 50% reduction in global pSer2.DOI:http://dx.doi.org/10.7554/eLife.06535.011

Mentions: Indeed, i-CDK9 gradually decreased the amounts of HEXIM1 bound to CDK9-F and at the same time increased the BRD4-CDK9-F binding in a dosage-dependent manner (Figure 4A). Just like the induction of MYC expression (Figure 3B), the disruption of 7SK snRNP and formation of BRD4-P-TEFb were highly sensitive to i-CDK9 and required as little as 0.1 μM of the drug (Figure 4A, compare lane 8 to lane 6). At this concentration, i-CDK9 only slightly decreased the global pSer2 level (Figure 4A, compare between lanes 1 and 3) but began to markedly induce MYC expression (Figure 3B). In a time course analysis, i-CDK9 (0.3 μM)-induced disruption of 7SK snRNP at a time point (1 hr) that was much earlier than that required to cause about 50% reduction in global pSer2 (8 hr; Figure 4—figure supplement 1). Together, these results reveal the remarkable efficiency with which i-CDK9 induces the transfer of P-TEFb from 7SK snRNP to BRD4.


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)

i-CDK9 (0.3 μM) induces disruption of 7SK snRNP at a time point much earlier than that required to cause about 50% reduction in global pSer2.DOI:http://dx.doi.org/10.7554/eLife.06535.011
© Copyright Policy
Related In: Results  -  Collection

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

fig4s1: i-CDK9 (0.3 μM) induces disruption of 7SK snRNP at a time point much earlier than that required to cause about 50% reduction in global pSer2.DOI:http://dx.doi.org/10.7554/eLife.06535.011
Mentions: Indeed, i-CDK9 gradually decreased the amounts of HEXIM1 bound to CDK9-F and at the same time increased the BRD4-CDK9-F binding in a dosage-dependent manner (Figure 4A). Just like the induction of MYC expression (Figure 3B), the disruption of 7SK snRNP and formation of BRD4-P-TEFb were highly sensitive to i-CDK9 and required as little as 0.1 μM of the drug (Figure 4A, compare lane 8 to lane 6). At this concentration, i-CDK9 only slightly decreased the global pSer2 level (Figure 4A, compare between lanes 1 and 3) but began to markedly induce MYC expression (Figure 3B). In a time course analysis, i-CDK9 (0.3 μM)-induced disruption of 7SK snRNP at a time point (1 hr) that was much earlier than that required to cause about 50% reduction in global pSer2 (8 hr; Figure 4—figure supplement 1). Together, these results reveal the remarkable efficiency with which i-CDK9 induces the transfer of P-TEFb from 7SK snRNP to BRD4.

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