Journal
ONCOGENE
Volume 30, Issue 4, Pages 471-481Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.423
Keywords
FADD; Plk1; phosphorylation; tumor suppressor; negative feedback
Funding
- 21C Frontier Functional Human Genome Project [FG09-21-02]
- Center for Biological Modulators [CMB34-A2300-01-00-00]
- National Research foundation at the Ministry of Education, Science and Technology in Korea [2009-0093957]
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Phosphorylation of the Fas-associated death domain (FADD) protein sensitizes cancer cells to various chemotherapeutics. However, the molecular mechanism underlying chemosensitization by phosphorylated FADD (P-FADD) is poorly understood. In this study, we describe the physical interactions and functional interplay between Polo-like kinase 1 (Plk1) and FADD. Plk1 phosphorylates FADD at Ser-194 in response to treatment with taxol. Overexpression of a phosphorylation-mimicking mutant, FADD S194D, caused degradation of Plk1 in an ubiquitin-independent manner, and delayed cytokinesis, consistent with the expected cellular phenotype of Plk1 deficiency. This demonstrates that Plk1 is regulated via a negative feedback loop by its substrate, FADD. Overexpression of FADD S194D sensitized HeLa cells to a low dose of taxol independently of caspase activation, whereas overexpression of FADD S194D resulted in caspase activation in response to a high dose of taxol. Therefore, we examined whether the death potential of P-FADD affected Plk1-mediated tumorigenesis. Transfection of FADD S194D inhibited colony formation by Plk1-overexpressing HeLa cells (HeLa-Plk1). Moreover, overexpression of FADD S194D suppressed tumorigenesis in nude mice xenografted with HeLa-Plk1. Therefore, this study reports the first in vivo validation of tumor-suppressing activity of P-FADD. Collectively, our data demonstrate that in response to taxol, Plk1 endows death-promoting and tumor-suppressor functions to its substrate, FADD. Oncogene (2011) 30, 471-481; doi: 10.1038/onc.2010.423; published online 4 October 2010
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