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Published on: January 7, 2019
Link of Dlk/ZIP kinase to cell apoptosis and tumor suppression
1State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, and Department of Gynecology and Obstetrics, Shanghai First People Hospital, Shanghai 200433, PR China.
Abstract:
Death-associated protein kinase (DAPk) family has emerged as a novel subfamily of pro-apoptotic serine/threonine kinase in the last 10 years. Although the functions of DAPk have been well documented, those of other family members remain uncertain. In this work, we characterized the expression pattern of human DAPk like kinase/Zipper interacting protein kinase (Dlk/ZIP kinase) in cancer specimens and cell lines. Dlk expression level was significantly down-regulated in cervical carcinoma cells compared to the surrounding non-tumorous tissues. Overexpression of Dlk led to cell morphological changes, suppressed colony formation and elevated cell apoptosis in cancer cell lines. Both the kinase activity and the cytoplasmic localization were required for its pro-apoptotic tendency. Mechanism exploration revealed that upon serum deprivation, Dlk overexpression could sensitize cells to apoptosis while overexpression of the kinase inactive mutant (Dlk-K42A) was able to rescue apoptotic cell death. Our data thus implicates that Dlk plays a positive role in modulating death-related signaling pathways. Reconstitution of Dlk expression might bring a potential therapeutic approach to cervical carcinoma treatments.
Insights
Human DAPk-like kinase (Dlk) is down-regulated in cervical cancer. Its overexpression induces apoptosis and suppresses tumor growth, suggesting Dlk as a potential therapeutic target for cervical carcinoma.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The Death-associated protein kinase (DAPk) family comprises pro-apoptotic serine/threonine kinases.
- While DAPk functions are known, other family members' roles, including Dlk/ZIP kinase, are less understood.
- Investigating Dlk's role in cancer is crucial for understanding cell death pathways.
Purpose of the Study:
- To characterize the expression pattern of human Dlk/ZIP kinase in cervical cancer.
- To elucidate the functional role of Dlk in cancer cell apoptosis and proliferation.
- To explore the mechanism underlying Dlk's pro-apoptotic activity.
Main Methods:
- Analysis of Dlk expression in cervical carcinoma tissues and cell lines.
- Overexpression studies of Dlk and its kinase-inactive mutant (Dlk-K42A) in cancer cells.
- Assessment of cell morphology, colony formation, and apoptosis induction.
- Investigation of Dlk's localization and kinase activity requirements for apoptosis.
Main Results:
- Dlk expression was significantly downregulated in cervical carcinoma compared to normal tissues.
- Dlk overexpression induced morphological changes, suppressed colony formation, and increased apoptosis in cancer cells.
- Both kinase activity and cytoplasmic localization of Dlk were essential for its pro-apoptotic function.
Conclusions:
- Dlk acts as a pro-apoptotic kinase, playing a positive role in death-related signaling.
- Downregulation of Dlk contributes to cervical carcinoma development.
- Restoring Dlk expression presents a potential therapeutic strategy for cervical cancer.
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