myc Boxes, Which Are Conserved in myc Family Proteins, Are Signals for Protein Degradation via the Proteasome

ABSTRACT

Cellular levels of the rapidly degraded c-myc protein play an important role in determining the proliferation status of cells. Increased levels of c-myc are frequently associated with rapidly proliferating tumor cells. We show here that myc boxes I and II, found in the N termini of all members of the myc protein family, function to direct the degradation of the c-myc protein. Both myc boxes I and II contain sufficient information to independently direct the degradation of otherwise stably expressed proteins to which they are fused. At least part of the myc box-directed degradation occurs via the proteasome. The mechanism of myc box-directed degradation appears to be conserved between yeast and mammalian cells. Our results suggest that the myc boxes may play an important role in regulating the level and activity of the c-myc protein.

ACKNOWLEDGMENTS

We thank W. Hörz (Ludwig-Maximilians Universität, Munich, Germany), C. Goding (Marie Curie Research Institute, United Kingdom), T. Almlöf (Karolinska Institute), and P. Ljungdahl (Ludwig Institute for Cancer Research, Stockholm, Sweden) for plasmids; W. Hilt (Universität Stuttgart, Stuttgart, Germany) and W. Hörz for yeast strains; A.-C. Wikström (Karolinska Institute) and C. Gooding for antibodies; and G. Mason (Bristol University, Bristol, United Kingdom) for the inhibitor Z-L₃VS. We thank S. Hermann for critically reading the manuscript and members of the Steroid Receptor Group and the Yeast Molecular Genetics Group for useful discussions and technical advice.

This work was supported by a grant from the Swedish Cancer Fund (3831-B97-02YBB).