In:
eLife, eLife Sciences Publications, Ltd, Vol. 4 ( 2015-06-17)
Abstract:
Cancers are often caused by mutations in genes that allow cells to proliferate uncontrollably. One gene that is frequently mutated in many cancers encodes a protein called MYC. The activity of this gene is normally tightly controlled, but the mutations found in human cancer cells mean that this gene is constantly switched on, and so too much MYC protein is produced. Previous studies have shown that a protein complex called ‘positive transcription elongation factor b’ (or P-TEFb for short) is essential to control the expression of the gene for MYC. P-TEFb works with an enzyme called RNA polymerase II to copy the instructions contained in protein-coding genes into long molecules called messenger RNAs. This process is called transcription and it involves a number of stages. P-TEFb is needed to start of one these stages, which is known as the ‘elongation’ step. P-TEFb consists of two protein subunits; one of which—an enzyme called CDK9—is the catalytic subunit. Most of the P-TEFb complexes in a cell are held in an inactive form, in which the activity of the CDK9 subunit is suppressed. If CDK9 is active when it should not be, certain proteins—including the MYC protein—can be produced in abnormally high amounts. This means that inhibiting CDK9 has been investigated as one way to reduce the production of the MYC protein. While some CDK9 inhibitors already exist, these compounds have the undesirable effect of also inhibiting other related enzymes and thus killing normal cells. Hence, new and more selective inhibitors of CDK9 are urgently needed. Lu, Xue et al. have now developed a new inhibitor of CDK9, called i-CDK9. The experiments show that i-CDK9 can potently inhibit CDK9 activity; and in human cells, very low levels of i-CDK9 prevented RNA polymerase II carrying out elongation for many genes. Unexpectedly, Lu, Xue et al. observed that more messenger RNA molecules that encode MYC were produced after cells were treated with low levels of i-CDK9. Further investigation revealed that this unexpected result occurred because the P-TEFb complexes were released from the inactive form and brought to the MYC gene by another protein called BRD4. This stimulated production of the MYC messenger RNAs. When P-TEFb was bound by BRD4, the CDK9 activity was also protected against inhibition by i-CDK9. Moreover, the reason that the MYC expression was induced by i-CDK9 is because the cells can compensate for the loss of CDK9 by using MYC to maintain the production of messenger RNAs of many key genes; these genes include the gene for MYC itself. These results suggest that CDK9 and MYC must be simultaneously inhibited in order to effectively treat cancers.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.06535.001
DOI:
10.7554/eLife.06535.002
DOI:
10.7554/eLife.06535.003
DOI:
10.7554/eLife.06535.004
DOI:
10.7554/eLife.06535.005
DOI:
10.7554/eLife.06535.006
DOI:
10.7554/eLife.06535.007
DOI:
10.7554/eLife.06535.008
DOI:
10.7554/eLife.06535.009
DOI:
10.7554/eLife.06535.010
DOI:
10.7554/eLife.06535.011
DOI:
10.7554/eLife.06535.012
DOI:
10.7554/eLife.06535.013
DOI:
10.7554/eLife.06535.014
DOI:
10.7554/eLife.06535.015
DOI:
10.7554/eLife.06535.016
DOI:
10.7554/eLife.06535.017
DOI:
10.7554/eLife.06535.018
DOI:
10.7554/eLife.06535.019
DOI:
10.7554/eLife.06535.020
DOI:
10.7554/eLife.06535.021
DOI:
10.7554/eLife.06535.022
DOI:
10.7554/eLife.06535.023
DOI:
10.7554/eLife.06535.024
DOI:
10.7554/eLife.06535.025
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2015
detail.hit.zdb_id:
2687154-3
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