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Cables1 controls p21/Cip1 protein stability by antagonizing proteasome subunit alpha type 3
11] Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China [2] Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
Abstract:
The cyclin-dependent kinase (CDK) inhibitor 1A, p21/Cip1, is a vital cell cycle regulator, dysregulation of which has been associated with a large number of human malignancies. One critical mechanism that controls p21 function is through its degradation, which allows the activation of its associated cell cycle-promoting kinases, CDK2 and CDK4. Thus delineating how p21 is stabilized and degraded will enhance our understanding of cell growth control and offer a basis for potential therapeutic interventions. Here we report a novel regulatory mechanism that controls the dynamic status of p21 through its interaction with Cdk5 and Abl enzyme substrate 1 (Cables1). Cables1 has a proposed role as a tumor suppressor. We found that upregulation of Cables1 protein was correlated with increased half-life of p21 protein, which was attributed to Cables1/p21 complex formation and supported by their co-localization in the nucleus. Mechanistically, Cables1 interferes with the proteasome (Prosome, Macropain) subunit alpha type 3 (PSMA3) binding to p21 and protects p21 from PSMA3-mediated proteasomal degradation. Moreover, silencing of p21 partially reverses the ability of Cables1 to induce cell death and inhibit cell proliferation. In further support of a potential pathophysiological role of Cables1, the expression level of Cables1 is tightly associated with p21 in both cancer cell lines and human lung cancer patient tumor samples. Together, these results suggest Cables1 as a novel p21 regulator through maintaining p21 stability and support the model that the tumor-suppressive function of Cables1 occurs at least in part through enhancing the tumor-suppressive activity of p21.
Insights
Cables1 protein stabilizes p21/Cip1, a key cell cycle regulator, by preventing its degradation. This interaction enhances p21’s tumor-suppressive activity, offering potential therapeutic avenues for cancer.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- p21/Cip1 is a critical cell cycle regulator, and its dysregulation is linked to human cancers.
- p21/Cip1 degradation is a key mechanism controlling its function and the activity of cell cycle-promoting kinases.
- Understanding p21/Cip1 stabilization and degradation is crucial for cell growth control and therapeutic strategies.
Purpose of the Study:
- To elucidate a novel regulatory mechanism controlling p21/Cip1 stability.
- To investigate the role of Cables1 (Cdk5 and Abl enzyme substrate 1) in p21/Cip1 regulation.
- To explore the potential tumor-suppressive function of Cables1 through its interaction with p21/Cip1.
Main Methods:
- Assessed the correlation between Cables1 protein levels and p21/Cip1 half-life.
- Investigated Cables1/p21/Cip1 complex formation and nuclear co-localization.
- Examined the effect of Cables1 on PSMA3-mediated proteasomal degradation of p21/Cip1.
- Evaluated the impact of p21/Cip1 silencing on Cables1-induced cell death and proliferation inhibition.
- Analyzed Cables1 and p21/Cip1 expression in cancer cell lines and human lung cancer samples.
Main Results:
- Upregulation of Cables1 protein correlated with increased p21/Cip1 half-life.
- Cables1 formed a complex with p21/Cip1 in the nucleus, protecting it from PSMA3-mediated proteasomal degradation.
- Silencing p21/Cip1 partially reversed Cables1's effects on cell death and proliferation.
- Cables1 and p21/Cip1 expression levels were tightly associated in cancer cell lines and patient tumor samples.
Conclusions:
- Cables1 acts as a novel regulator of p21/Cip1 by maintaining its stability.
- Cables1's tumor-suppressive function is, at least in part, mediated by enhancing p21/Cip1's tumor-suppressive activity.
- The Cables1-p21/Cip1 regulatory axis represents a potential target for cancer therapeutics.
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