Editors' ChoiceTranscription factors

Promoting Exchange through Degradation

Science's STKE  12 Mar 2002:
Vol. 2002, Issue 123, pp. tw106-TW106
DOI: 10.1126/stke.2002.123.tw106

Transcription factor activity is regulated by interactions with cofactors, such that a given transcription factor may have both activator and repressor activities, depending on the cofactors present. Ostendorff et al. show that the repressive cofactor for the LIM homeodomain transcription factor (LIMTF), RING finger LIM domain-binding protein (RLIM), exhibits E3 ligase activity in vitro, resulting in the conjugation of ubiquitin to itself and two other LIMTF cofactors, CLIM and LMO, both of which serve to activate transcription. Overexpression of RLIM promoted CLIM and LMO degradation, and inhibition of RLIM (through transfection of dominant-negative mutants or RNA interference-mediated gene repression) resulted in enhanced CLIM immunofluorescence, suggesting increased protein abundance. Expression of RLIM inhibited reporter gene expression through both a CLIM-dependent and a CLIM-independent mechanism. The CLIM-dependent mechanism required an intact RING finger domain, whereas the CLIM-independent mechanism, which most likely involved recruitment of the histone deacetylase Sin3A, did not require the RING finger domain and most likely was not dependent on the E3 activity of RLIM. The last experiments in the paper attempted to determine DNA binding of the various cofactors and LIMTF and how RLIM affected these interactions. DNA binding of LIMTF and CLIM were inhibited in the presence of RLIM and an E2 ubiquitin conjugation enzyme, suggesting that RLIM can promote the ubiquitination and dissociation of the LIMTF-CLIM complex. Thus, ubiquitination by RLIM may represent one mechanism for promoting the exchange of cofactors on LIMTF.

H. P. Ostandorff, R. I. Peirano, M. A. Peters, A. Schlüter, M. Bossenz, M. Scheffner, I. Bach, Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors. Nature 416, 99-103 (2002). [Online Journal]