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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM
1Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
Abstract:
Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements. However, because of its binding to E2F and CHR elements, DREAM regulates a larger set of target genes leading to regulatory functions distinct from pRB/E2F. The p53-DREAM pathway controls more than 250 mostly cell cycle-associated genes. The functional spectrum of these pathway targets spans from the G1 phase to the end of mitosis. Consequently, through downregulating the expression of gene products which are essential for progression through the cell cycle, the p53-DREAM pathway participates in the control of all checkpoints from DNA synthesis to cytokinesis including G1/S, G2/M and spindle assembly checkpoints. Therefore, defects in the p53-DREAM pathway contribute to a general loss of checkpoint control. Furthermore, deregulation of DREAM target genes promotes chromosomal instability and aneuploidy of cancer cells. Also, DREAM regulation is abrogated by the human papilloma virus HPV E7 protein linking the p53-DREAM pathway to carcinogenesis by HPV. Another feature of the pathway is that it downregulates many genes involved in DNA repair and telomere maintenance as well as Fanconi anemia. Importantly, when DREAM function is lost, CDK inhibitor drugs employed in cancer treatment such as Palbociclib, Abemaciclib and Ribociclib can compensate for defects in early steps in the pathway upstream from cyclin/CDK complexes. In summary, the p53-p21-DREAM-E2F/CHR pathway controls a plethora of cell cycle genes, can contribute to cell cycle arrest and is a target for cancer therapy.
Insights
The p53-p21-DREAM-E2F/CHR pathway, or p53-DREAM pathway, controls cell cycle genes to arrest cell growth. This pathway
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Biology
Background:
- The p53 tumor suppressor protein is crucial for cell cycle regulation.
- p53-mediated cell cycle arrest primarily occurs through transcriptional downregulation of cell cycle genes.
- The p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway) has emerged as a key regulator of p53-dependent gene repression.
Purpose of the Study:
- To elucidate the regulatory mechanisms and functional significance of the p53-DREAM pathway in cell cycle control.
- To investigate the role of the p53-DREAM pathway in maintaining genomic stability and its implications in cancer.
- To explore therapeutic strategies targeting the p53-DREAM pathway.
Main Methods:
- Analysis of gene expression regulated by the p53-DREAM pathway.
- Comparison of DREAM-mediated gene regulation with the retinoblastoma pRB/E2F pathway.
- Investigation of DREAM pathway's role in cell cycle checkpoints and chromosomal stability.
- Assessment of the impact of human papilloma virus (HPV) E7 on DREAM regulation.
- Evaluation of CDK inhibitor drugs in compensating for defects in the p53-DREAM pathway.
Main Results:
- The p53-DREAM pathway controls over 250 cell cycle-associated genes, spanning all phases of the cell cycle from G1 to mitosis.
- DREAM regulates a broader set of target genes than pRB/E2F due to its binding to both E2F and CHR promoter sites.
- Defects in the p53-DREAM pathway lead to loss of checkpoint control, promoting chromosomal instability and aneuploidy in cancer cells.
- HPV E7 abrogates DREAM regulation, linking the pathway to HPV-induced carcinogenesis.
- The pathway downregulates genes involved in DNA repair, telomere maintenance, and Fanconi anemia.
- CDK inhibitors like Palbociclib, Abemaciclib, and Ribociclib can compensate for upstream defects in the p53-DREAM pathway.
Conclusions:
- The p53-DREAM pathway is a critical regulator of numerous cell cycle genes, essential for cell cycle arrest and checkpoint control.
- Dysregulation of the p53-DREAM pathway contributes to genomic instability and cancer development.
- Targeting the p53-DREAM pathway presents a promising strategy for cancer therapy, with CDK inhibitors offering potential compensatory mechanisms.
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