Uncovering the role of APC-Cdh1 in generating the dynamics of S-phase onset.

Abstract

Cdh1, a coactivator of the anaphase-promoting complex (APC), is a potential tumor suppressor. Cdh1 ablation promotes precocious S-phase entry, but it was unclear how this affects DNA replication dynamics while contributing to genomic instability and tumorigenesis. We find that Cdh1 depletion causes early S-phase onset in conjunction with increase in Rb/E2F1-mediated cyclin E1 expression, but reduced levels of cyclin E1 protein promote this transition. We hypothesize that this is due to a weakened cyclin-dependent kinase inhibitor (CKI)-cyclin-dependent kinase 2 positive-feedback loop, normally generated by APC-Cdh1-mediated proteolysis of Skp2. Indeed, Cdh1 depletion increases Skp2 abundance while diminishing levels of the CKI p27. This lowers the level of cyclin E1 needed for S-phase entry and delays cyclin E1 proteolysis during S-phase progression while corresponding to slowed replication fork movement and reduced frequency of termination events. In summary, using both experimental and computational approaches, we show that APC-Cdh1 establishes a stimulus-response relationship that promotes S phase by ensuring that proper levels of p27 accumulate during G1 phase, and defects in its activation accelerate the timing of S-phase onset while prolonging its progression.

• Authors: Xi Yuan, Jeyaraman Srividhya, Thomas De Luca, Ju-Hyong E Lee, Joseph R Pomerening
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 25 Issue 4 Pg. 441-56 (Feb 2014) ISSN: 1939-4586 [Electronic] United States
• PMID: 24356446 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antigens, CD
• CCNE1 protein, human
• CDH1 protein, human
• Cadherins
• Cyclin E
• E2F1 Transcription Factor
• E2F1 protein, human
• Oncogene Proteins
• RNA, Small Interfering
• Retinoblastoma Protein
• S-Phase Kinase-Associated Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• Anaphase-Promoting Complex-Cyclosome
• CDK2 protein, human
• Cyclin-Dependent Kinase 2

Topics

• Anaphase-Promoting Complex-Cyclosome (genetics, metabolism)
• Antigens, CD
• Cadherins (antagonists & inhibitors, genetics, metabolism)
• Cell Transformation, Neoplastic (genetics, pathology)
• Cyclin E (genetics, metabolism)
• Cyclin-Dependent Kinase 2 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• DNA Replication
• E2F1 Transcription Factor (genetics, metabolism)
• Feedback, Physiological
• G1 Phase
• Gene Expression Regulation
• HeLa Cells
• Humans
• Oncogene Proteins (genetics, metabolism)
• Proteolysis
• RNA, Small Interfering (genetics, metabolism)
• Retinoblastoma Protein (genetics, metabolism)
• S Phase
• S-Phase Kinase-Associated Proteins (genetics, metabolism)
• Signal Transduction
• Time Factors