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J. Biol. Chem., Vol. 278, Issue 1, 27-36, January 3, 2003

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PAX3-FKHR Transformation Increases 26 S Proteasome-dependent Degradation of p27^Kip1, a Potential Role for Elevated Skp2 Expression^*

Lei Zhang and Chiayeng Wang

From the Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, Illinois 60612

PAX3-FKHR is an oncogenic form of the developmental regulator Pax3 transcription factor. PAX3-FKHR results from a t(2,13) chromosomal translocation, a unique genetic marker of alveolar rhabdomyosarcoma. In this study, we showed that ectopic expression of PAX3-FKHR, but not Pax3, in fibroblasts altered cell cycle control and accelerated G₀/G₁ to S cell cycle transition. PAX3-FKHR-expressing cells had reduced expression of p27^Kip1 protein, a key cell cycle regulator. The reduction in p27^Kip1 levels by PAX3-FKHR resulted from destabilization of p27^Kip1 as shown by cycloheximide treatment and in vivo pulse-chase labeling experiments. The reduced p27^Kip1 protein level in PAX3-FKHR-expressing cells was restored to the level of control cells by treatment with chemical inhibitors that specifically blocked 26 S proteasome activity. Along with the reduction in p27^Kip1 protein, PAX3-FKHR-expressing cells exhibited elevated expression of F-box Skp2 protein, a substrate-specific component of SCF (Skp1-Cullin-F box protein) ligase involved in the cell cycle-dependent control of p27^Kip1 ubiquitination and 26 S proteasome dependent degradation. Finally, we showed that ectopic expression of p27^Kip1 in PAX3-FKHR-expressing cells significantly reduced the proliferation and colony-forming potential of these cells, implicating that down-regulation of p27^Kip1 protein played an active role in the PAX3-FKHR-directed cell transformation.

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