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The apoptotic v-cyclin-CDK6 complex phosphorylates and inactivates Bcl-2
P M Ojala1, K Yamamoto, E Castaños-Vélez
1Haartman Institute & Biocentrum Helsinki, University of Helsinki, PO Box 21, Haartmaninkatu 3, 00014 Helsinki, Finland. Paivi.Ojala@helsinki.fi
Nature Cell Biology
|November 1, 2000
Summary
Kaposi's sarcoma herpesvirus (KSHV) v-cyclin inactivates cellular Bcl-2 through phosphorylation, promoting apoptosis. This mechanism, identified in KSHV-infected cells, disrupts host cell death pathways, potentially driving Kaposi's sarcoma development.
Area of Science:
- Virology
- Molecular Biology
- Cancer Research
Background:
- Kaposi's sarcoma-associated herpesvirus (KSHV) v-cyclin forms a complex with cyclin-dependent kinase 6 (CDK6), promoting cell cycle progression.
- This v-cyclin/CDK6 complex can induce apoptosis in cells with high CDK6 levels.
- KSHV encodes v-Bcl-2, which provides protection against this apoptosis.
Purpose of the Study:
- To investigate the interaction between KSHV v-cyclin/CDK6 and cellular Bcl-2.
- To determine the role of Bcl-2 phosphorylation in KSHV-induced apoptosis.
- To elucidate KSHV's strategy for evading host apoptotic pathways.
Main Methods:
- In vitro kinase assays to identify Bcl-2 as a v-cyclin/CDK6 substrate.
- Analysis of Bcl-2 phosphorylation status in KSHV-infected cells and Kaposi's sarcoma tissues.
- Site-directed mutagenesis of Bcl-2 phosphorylation sites (S70A S87A) to assess apoptotic resistance.
Main Results:
- Cellular Bcl-2 loses anti-apoptotic function due to inactivating phosphorylation in its loop region.
- Bcl-2 is identified as a novel substrate for the v-cyclin/CDK6 complex.
- A Bcl-2 mutant (S70A S87A) resistant to phosphorylation confers resistance to apoptosis.
- Phosphorylated Bcl-2 is detected in HHV8-positive Kaposi's sarcoma tissues.
Conclusions:
- KSHV v-cyclin/CDK6 inactivates cellular Bcl-2 via phosphorylation, contributing to apoptosis.
- This viral interference with host apoptosis signaling may promote Kaposi's sarcoma development.
- Targeting this viral mechanism could offer therapeutic strategies for Kaposi's sarcoma.