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Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis
S Zhong1, P Salomoni, S Ronchetti
1Department of Human Genetics and the Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
Abstract:
The promyelocytic leukemia protein (PML) gene of acute promyelocytic leukemia (APL) encodes a cell growth and tumor suppressor essential for multiple apoptotic signals. Daxx was identified as a molecule important for the cytoplasmic transduction of the Fas proapoptotic stimulus. Here, we show that upon mitogenic activation of mature splenic lymphocytes, Daxx is dramatically upregulated and accumulates in the PML nuclear body (NB) where PML and Daxx physically interact. In the absence of PML, Daxx acquires a dispersed nuclear pattern, and activation-induced cell death of splenocytes is profoundly impaired. PML inactivation results in the complete abrogation of the Daxx proapoptotic ability. In APL cells, Daxx is delocalized from the NB. Upon retinoic acid treatment, which induces disease remission in APL, Daxx relocalizes to the PML NBs. These results indicate that PML and Daxx cooperate in a novel NB-dependent pathway for apoptosis and shed new light in the role of PML in tumor suppression.
Insights
Promyelocytic leukemia protein (PML) and Daxx cooperate in nuclear bodies to promote apoptosis. PML is crucial for Daxx
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The promyelocytic leukemia protein (PML) gene is a tumor suppressor crucial for apoptosis.
- Daxx is involved in the Fas proapoptotic pathway.
Purpose of the Study:
- To investigate the interaction between PML and Daxx in apoptosis.
- To elucidate the role of PML nuclear bodies (NBs) in Daxx-mediated apoptosis.
Main Methods:
- Studied mitogenically activated splenic lymphocytes.
- Analyzed Daxx and PML localization in nuclear bodies.
- Assessed the impact of PML absence on Daxx function and apoptosis.
Main Results:
- Daxx accumulates in PML NBs upon lymphocyte activation, where PML and Daxx interact.
- PML absence causes dispersed nuclear Daxx and impairs activation-induced cell death.
- PML inactivation abrogates Daxx's proapoptotic function.
- In acute promyelocytic leukemia (APL) cells, Daxx delocalizes from NBs but relocalizes upon retinoic acid treatment.
Conclusions:
- PML and Daxx collaborate in a novel NB-dependent apoptotic pathway.
- PML is essential for Daxx's proapoptotic activity and nuclear localization.
- This interaction sheds light on PML's tumor suppressor functions and APL pathogenesis.