Functional overlap of sequences that activate transcription and signal ubiquitin-mediated proteolysis

^*Cold Spring Harbor Laboratory, 1 Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11724; and ^‡Graduate Program in Genetics, State University of New York, Stony Brook, New York 11792

Communicated by James D. Watson, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (received for review November 15, 1999)

Abstract

Many transcription factors, particularly those involved in the control of cell growth, are unstable proteins destroyed by ubiquitin-mediated proteolysis. In a previous study of sequences targeting the transcription factor Myc for destruction, we observed that the region in Myc signaling ubiquitin-mediated proteolysis overlaps closely with the region in Myc that activates transcription. Here, we present evidence that the overlap of these two activities is not unique to Myc, but reflects a more general phenomenon. We show that a similar overlap of activation domains and destruction elements occurs in other unstable transcription factors and report a close correlation between the ability of an acidic activation domain to activate transcription and to signal proteolysis. We also show that destruction elements from yeast cyclins, when tethered to a DNA-binding domain, activate transcription. The intimate overlap of activation domains and destruction elements reveals an unexpected convergence of two very different processes and suggests that transcription factors may be destroyed because of their ability to activate transcription.

Footnotes

↵ † Present address: Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577 Japan.
↵ § To whom reprint requests should be addressed. E-mail: tansey{at}cshl.org.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.050007597.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.050007597
Abbreviations:

DAD,

destruction and activation domain;

DBD,

DNA-binding domain;

TAD,

transcriptional activation domain;

Ub,

ubiquitin;

3AT,

3-amino-triazole;

HA,

hemagglutinin;

PS1,

proteasome inhibitor 1;

LLnL,

N-acetyl-Leu-Leu-norleucinal