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Molecular and Cellular Biology, November 1999, p. 7577-7588, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

PBX and MEIS as Non-DNA-Binding Partners in Trimeric Complexes with HOX Proteins

Kandavel Shanmugam,1,2 Nancy C. Green,1 Isabel Rambaldi,1 H. Uri Saragovi,1,3 and Mark S. Featherstone1,2,4,5,*

McGill Cancer Centre,1 Division of Experimental Medicine, Department of Medicine,2 and Departments of Pharmacology and Therapeutics,3 Oncology,4 and Biochemistry,5 McGill University, Montreal, Quebec, Canada H3G 1Y6

Received 22 March 1999/Returned for modification 5 May 1999/Accepted 21 July 1999

HOX, PBX, and MEIS transcription factors bind DNA through a homeodomain. PBX proteins bind DNA cooperatively as heterodimers with MEIS family members and also with HOX proteins from paralog groups 1 to 10. MEIS proteins cooperatively bind DNA with ABD-B class HOX proteins of groups 9 and 10. Here, we examine aspects of dimeric and higher-order interactions between these three homeodomain classes. The most significant results can be summarized as follows. (i) Most of PBX N terminal to the homeodomain is required for efficient cooperative binding with HOXD4 and HOXD9. (ii) MEIS and PBX proteins form higher-order complexes on a heterodimeric binding site. (iii) Although MEIS does not cooperatively bind DNA with ANTP class HOX proteins, it does form a trimer as a non-DNA-binding partner with DNA-bound PBX-HOXD4. (iv) The N terminus of HOXD4 negatively regulates trimer formation. (v) MEIS forms a similar trimer with DNA-bound PBX-HOXD9. (vi) A related trimer (where MEIS is a non-DNA-binding partner) is formed on a transcriptional promoter within the cell. (vii) We observe an additional trimer class involving non-DNA-bound PBX and DNA-bound MEIS-HOXD9 or MEIS-HOXD10 heterodimers that is enhanced by mutation of the PBX homeodomain. (viii) In this latter trimer, PBX is likely to contact both MEIS and HOXD9/D10. (ix) The stability of DNA binding by all trimers is enhanced relative to the heterodimers. These findings suggest novel functions for PBX and MEIS in modulating the function of DNA-bound MEIS-HOX and PBX-HOX heterodimers, respectively.

* Corresponding author. Mailing address: McGill Cancer Centre, McGill University, Montreal, Quebec, Canada H3G 1Y6. Phone: (514) 398-8937. Fax: (514) 398-6769. E-mail: mfeather{at}med.mcgill.ca.

Molecular and Cellular Biology, November 1999, p. 7577-7588, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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