The ETS Domain Transcription Factor Elk-1 Contains a Novel Class of Repression Domain

Abstract

The ETS domain transcription factor Elk-1 serves as an integration point for different mitogen-activated protein (MAP) kinase pathways. Phosphorylation of Elk-1 by MAP kinases triggers its activation. However, while the activation process is well understood, its downregulation-inactivation is less well characterized. The ETS DNA-binding domain plays a role in the downregulation of Elk-dependent promoter activity following mitogenic activation by recruiting the mSin3A-HDAC complex. Here we have identified a novel evolutionarily conserved repression domain in Elk-1, termed the R motif, which serves to reduce the basal transcriptional activity of Elk-1 and dampen its response to mitogenic signals. This domain is highly potent and portable and can repress transcription in trans. The R motif is related to the CRD1 repression domain in p300 and can functionally replace this domain and confer p21^waf1/cip1 inducibility on p300. However, the R motif acts in a context-dependent manner and is not p21^waf1/cip1 responsive in Elk-1. Thus, the Elk-1 R motif and the p300 CRD1 motif represent a new class of repression domains that are regulated in a context-dependent manner.

We thank Linda Shore for excellent technical assistance; Stefan Roberts and members of our laboratories for comments on the manuscript and stimulating discussions; and A. J. Whitmarsh, R. J. Davis, J. Hassell, C. Lemercier, S. Kochbin, P. Shaw, P. Tan. and K.-H. Klempnauer for reagents.

This work was supported by an MRC-funded PhD studentship (D.C.B.), grants from the Cancer Research Campaign [CRC] (N.D.P.), the Wellcome Trust (A.D.S.), a Royal Society University Research Fellowship (N.D.P.), and a Lister Institute of Preventive Medicine Research Fellowship to A.D.S.