Control of senescence by CXCR2 and its ligands
Juan C Acosta1, Ana O'Loghlen, Ana Banito
1Cell Proliferation Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom.
Abstract:
Senescence is an irreversible growth arrest with important physiological implications as it contributes to tumour suppression and may have a role in aging. During senescence, cells suffer profound phenotypic changes affecting amongst others cell morphology and chromatin structure. Senescent cells also undergo significant transcriptional changes, such as the increased production of a plethora of different secreted factors, which are the basis of the so-called senescence-associated secretory phenotype. While some of these factors have been previously shown to possess different pro-tumorigenic activities, we recently demonstrated that the secretion of CXCR2-binding chemokines (such as IL-8 or GROalpha) by senescent cells contribute to reinforce senescence via activation of the p53 pathway. Importantly, our data adds to that presented by several groups suggesting that also other factors secreted during senescence (such as PAI-1, IGFBP-7 or IL-6) contribute to the senescent response. Here, we discuss our findings in the context of the emerging role for secreted factors in regulating senescence through paracrine and/or autocrine mechanisms.
Insights
Cellular senescence, a state of irreversible growth arrest, involves significant changes including the secretion of factors that can reinforce the senescent state. These secreted factors play crucial roles in tumor suppression and aging.
Area of Science:
- Cellular Biology
- Molecular Biology
- Aging Research
Background:
- Cellular senescence is a critical process involved in tumor suppression and aging.
- Senescence triggers profound cellular changes, including altered morphology, chromatin structure, and gene expression.
- Senescent cells exhibit a senescence-associated secretory phenotype (SASP), characterized by the release of various factors.
Purpose of the Study:
- To investigate the role of secreted factors in regulating senescence.
- To explore the contribution of CXCR2-binding chemokines to senescence reinforcement.
- To contextualize findings within the broader understanding of paracrine and autocrine senescence regulation.
Main Methods:
- Analysis of transcriptional changes in senescent cells.
- Investigation of secreted factors, including chemokines like IL-8 and GROalpha.
- Assessment of the p53 pathway activation in response to secreted factors.
Main Results:
- Senescent cells secrete CXCR2-binding chemokines that reinforce senescence via p53 pathway activation.
- Other secreted factors like PAI-1, IGFBP-7, and IL-6 also contribute to the senescent response.
- Demonstrated the importance of secreted factors in paracrine and autocrine senescence regulation.
Conclusions:
- Secreted factors play a significant role in modulating cellular senescence.
- CXCR2-binding chemokines are key mediators in reinforcing senescence.
- Understanding SASP components is crucial for aging and cancer research.
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