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The c-MYC-AP4-p21 cascade

Peter Jung1, Heiko Hermeking

  • 1Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.

Cell Cycle (Georgetown, Tex.)
|March 10, 2009
PubMed

Insights

The c-MYC protein represses the p21 gene by inducing the AP4 transcription factor. AP4 then binds near the p21 promoter, inhibiting its expression and promoting cell cycle progression, particularly in colorectal cancer.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Gene Regulation

Background:

  • The p21 gene encodes a cyclin-dependent kinase (CDK) inhibitor, crucial for anti-proliferative responses.
  • c-MYC is known to promote cell cycle progression, but its mechanism for repressing p21 has been under investigation.

Purpose of the Study:

  • To elucidate the novel mechanism by which c-MYC represses p21 transcription.
  • To explore the role of the transcription factor AP4 (TFAP4) in this process.
  • To discuss the implications of the c-MYC-AP4-p21 axis in colorectal cancer.

Main Methods:

  • Investigated the transcriptional cascade initiated by c-MYC.
  • Identified AP4 (TFAP4) as a direct target gene of c-MYC.
  • Analyzed the binding of AP4 to the p21 promoter region.
  • Examined the functional consequences of AP4-mediated p21 repression.

Main Results:

  • c-MYC directly induces the expression of the AP4 transcription factor.
  • AP4 binds to motifs near the p21 promoter, mediating transcriptional repression.
  • AP4 interferes with p21 induction via DNA damage/p53 and TGFbeta/Smad pathways, and during differentiation.
  • Expression patterns of c-MYC and AP4 overlap in colonic epithelium and colorectal cancer.

Conclusions:

  • A novel mechanism reveals c-MYC represses p21 via AP4 induction, facilitating cell cycle progression.
  • AP4 plays a key role in c-MYC's function and is implicated in colorectal cancer.
  • The c-MYC-AP4 pathway presents potential targets for cancer diagnosis and therapy.

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