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A node between proliferation, apoptosis, and growth arrest
1Medicine Branch, National Cancer Institute, Bldg. 10, R 12N226, NIH, Bethesda, Maryland 20892, USA. mikhailb@box-m.nih.gov
Abstract:
Paradoxically, oncogenes and growth factors can induce proliferation and promote cellular survival but can also cause apoptosis and growth arrest. What determines whether a cell decides to proliferate, arrest growth, or die? Mitogens and activators of mitogen-activated pathways initiate the simultaneous production of proliferative (cyclins) and anti-proliferative (CDK inhibitors such as p21WAF1/CIP1) signals. Quiescent cells may respond to these signals by proliferation whereas proliferating cells may respond by growth arrest. Although pro-apoptotic oncoproteins, which constitute the downstream pathway (cyclin D, E2F, c-myc) directly induce proliferation, the activation of the upstream steps (growth factor receptors, Ras, cytoplasmic kinases) is required to prevent apoptosis.
Insights
Cellular fate is determined by a balance of growth and death signals. Oncogenes and growth factors can trigger proliferation or apoptosis, depending on pathway activation and cell state.
Area of Science:
- Cell Biology
- Molecular Oncology
Background:
- Oncogenes and growth factors paradoxically influence cell fate, promoting survival and proliferation, yet also inducing apoptosis and growth arrest.
- The decision between proliferation, growth arrest, or apoptosis is complex and not fully understood.
Purpose of the Study:
- To investigate the signaling pathways that determine whether a cell proliferates, arrests growth, or undergoes apoptosis.
- To elucidate the role of simultaneous proliferative and anti-proliferative signals in cellular decision-making.
Main Methods:
- Analysis of mitogen-activated pathways.
- Examination of the interplay between cyclins and cyclin-dependent kinase inhibitors (e.g., p21WAF1/CIP1).
- Investigation of upstream (growth factor receptors, Ras, cytoplasmic kinases) and downstream (cyclin D, E2F, c-myc) oncoprotein signaling.
Main Results:
- Mitogens trigger concurrent production of proliferative signals (cyclins) and anti-proliferative signals (CDK inhibitors like p21WAF1/CIP1).
- Quiescent cells may respond to these signals with proliferation, while proliferating cells may undergo growth arrest.
- Upstream pathway activation (growth factor receptors, Ras, cytoplasmic kinases) is crucial for preventing apoptosis, despite the presence of pro-apoptotic oncoproteins.
Conclusions:
- Cellular fate decisions are regulated by the dynamic balance of opposing signaling pathways.
- The cellular context (quiescent vs. proliferating) influences the response to mitogenic signals.
- Coordinated activation of upstream and downstream signaling is essential for cell survival and proliferation control.