Dataset Information

C-MYC-Induced AP4 Attenuates DREAM-Mediated Repression by p53.

ABSTRACT:

Background

The deregulated expression of the c-MYC oncogene activates p53, which is presumably mediated by ARF/INK4, as well as replication-stress-induced DNA damage. Here, we aimed to determine whether the c-MYC-inducible AP4 transcription factor plays a role in this context using a genetic approach.

Methods

We used a CRISPR/Cas9 approach to generate AP4- and/or p53-deficient derivatives of MCF-7 breast cancer cells harboring an ectopic, inducible c-MYC allele. Cell proliferation, senescence, DNA damage, and comprehensive RNA expression profiles were determined after activation of c-MYC. In addition, we analyzed the expression data from primary breast cancer samples.

Results

Loss of AP4 resulted in elevated levels of both spontaneous and c-MYC-induced DNA damage, senescence, and diminished cell proliferation. Deletion of p53 in AP4-deficient cells reverted senescence and proliferation defects without affecting DNA damage levels. RNA-Seq analyses showed that loss of AP4 enhanced repression of DREAM and E2F target genes after p53 activation by c-MYC. Depletion of p21 or the DREAM complex component LIN37 abrogated this effect. These p53-dependent effects were conserved on the level of clinical and gene expression associations found in primary breast cancer tumors.

Conclusions

Our results establish AP4 as a pivotal factor at the crossroads of c-MYC, E2F, and p53 target gene regulation.

SUBMITTER: Kaller M

PROVIDER: S-EPMC9954515 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

c-MYC-Induced AP4 Attenuates DREAM-Mediated Repression by p53.

Kaller Markus M Shi Wenjing W Hermeking Heiko H

Cancers 20230211 4

<h4>Background</h4>The deregulated expression of the c-MYC oncogene activates p53, which is presumably mediated by ARF/INK4, as well as replication-stress-induced DNA damage. Here, we aimed to determine whether the c-MYC-inducible AP4 transcription factor plays a role in this context using a genetic approach.<h4>Methods</h4>We used a CRISPR/Cas9 approach to generate <i>AP4</i>- and/or <i>p53</i>-deficient derivatives of MCF-7 breast cancer cells harboring an ectopic, inducible c-MYC allele. Cell ...[more]

PMID: 36831504

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