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Preparation and In Vitro Characterization of Magnetized miR-modified Endothelial Cells
Published on: May 2, 2017
miR-129 targets CDK1 and iASPP to modulate Burkitt lymphoma cell proliferation in a TAp63-dependent manner
Hui Zou1, Runying Zou1, Keke Chen1
1Department of Hematology and Oncology of Children's Medical Center, The First Affiliated Hospital of Hunan Normal University/Hunan Provincial People's Hospital, Changsha, Hunan, China.
Abstract:
Burkitt lymphoma is one of the most common lymphatic system cancers with poor outcome in adult patients. p53-induced apoptosis is a critical signaling for preventing tumor development. Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53. However, p53 is frequently mutated in Burkitt lymphoma, which gains novel oncogenic properties. Recently, the p53 family member, p63, became an attractive gene for the therapeutic strategies for patients with cancer. Therefore, we investigated the role of iASPP in the transactivation domain p63 (TAp63)-dependent cell proliferation inhibition in Burkitt lymphoma. We verified that the oncogenic effect of iASPP on Burkitt lymphoma is TAp63 dependent rather than p53 and confirmed that the interaction between CDK1 and iASPP enhanced the inhibitory effect of iASPP on p53 and TAp63. An online tool predicated that miR-129 might bind to 3'-untranslated region of iASPP and CDK1. We revealed that miR-129 acted as a tumor suppressor by inhibiting cancer cell proliferation and inhibiting CDK1 and iASPP via direct binding. An miR-129 inhibitor increased nucleus iASPP and decreased nucleus p53 and TAp63 levels, which could be reversed by the CDK1 knockdown, indicating that miR-129 might target CDK1 to inhibit iASPP phosphorylation, thus hindering iASPP nucleus localization and its inhibitory effect on p53 and TAp63 protein levels. Taken together, miR-129 could targetedly inhibit the expression of CDK1 and iASPP. CDK1 knockdown inhibits iASPP S84/S113 phosphorylation, thus blocking iASPP nucleus localization, suppressing the inhibitory effect of iASPP on p53 and TAp63, and restoring TAp63-induced proliferation inhibition in Burkitt lymphoma cells.
Insights
MicroRNA-129 suppresses Burkitt lymphoma by targeting CDK1 and iASPP, restoring TAp63-mediated cell proliferation inhibition. This finding offers a potential therapeutic strategy for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Burkitt lymphoma is an aggressive cancer with poor outcomes in adults.
- p53-induced apoptosis is crucial for tumor suppression, but p53 is often mutated in Burkitt lymphoma.
- The p53 family member, p63, is a potential therapeutic target in cancer.
Purpose of the Study:
- To investigate the role of iASPP in TAp63-dependent cell proliferation inhibition in Burkitt lymphoma.
- To elucidate the regulatory mechanism of iASPP and TAp63 by microRNA-129.
Main Methods:
- Verification of iASPP's oncogenic effect dependency on TAp63.
- Analysis of the interaction between CDK1 and iASPP.
- In silico prediction and experimental validation of miR-129 binding to iASPP and CDK1.
- Assessment of miR-129 inhibitor and CDK1 knockdown effects on protein levels and localization.
Main Results:
- iASPP promotes Burkitt lymphoma proliferation in a TAp63-dependent manner.
- miR-129 acts as a tumor suppressor by inhibiting CDK1 and iASPP expression and cancer cell proliferation.
- miR-129 targets CDK1, reducing iASPP phosphorylation and nuclear localization, thereby diminishing its inhibitory effect on p53 and TAp63.
Conclusions:
- miR-129 directly inhibits CDK1 and iASPP expression in Burkitt lymphoma.
- Targeting CDK1 by miR-129 restores TAp63-induced proliferation inhibition, highlighting miR-129 as a potential therapeutic agent.
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