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Molecular and Cellular Biology, June 2002, p. 3577-3589, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3577-3589.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification of Novel Isoforms of the BH3 Domain Protein Bim Which Directly Activate Bax To Trigger Apoptosis

Michela Marani,1 Tencho Tenev,1,{dagger} David Hancock,2 Julian Downward,2 and Nicholas R. Lemoine1*

Molecular Oncology Unit, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN,1 Signal Transduction Laboratory, Cancer Research UK, London WC2A 3PX, United Kingdom2

Received 6 August 2001/ Returned for modification 7 September 2001/ Accepted 4 March 2002

Bim (Bcl-2-interacting mediator of cell death) is a member of the BH3 domain-only subgroup of Bcl-2 family members, for which three splice variants have been described. Bim is expressed in many healthy cell types, where it is maintained in an inactive conformation through binding to the microtubule-associated dynein motor complex. Upon certain apoptotic stimuli, Bim is released from microtubules and mediates caspase-dependent apoptosis through a mechanism that is still unclear. Here, we have identified and characterized novel splice variants of human Bim mRNA. In particular, we show that a newly discovered, small protein isoform, BimAD, is also able to induce apoptosis strongly in several human cell lines. BimAD and the previously characterized isoform BimS are shown to be capable of heterodimerizing in vivo with both death antagonists (Bcl-2 and Bcl-XL) and death agonists (Bax). Mutants of BimAD that bind to Bax but not to Bcl-2 still promote apoptosis, indicating that Bim can regulate apoptosis through direct activation of the Bax-mediated cell death pathway without interaction with antiapoptotic Bcl-2 family members. Furthermore, we have shown that the interaction of the BimS and BimAD isoforms with Bax leads to a conformational change in this protein analogous to that triggered by the BH3-only protein Bid.

* Corresponding author. Mailing address: Molecular Oncology Unit, Imperial College School of Medicine, Hammersmith Hospital, DuCane Road, London W12 0NN, United Kingdom. Phone: 44(0)2083833975. Fax: 44(0)2083833258. E-mail: nick.lemoine{at}cancer.org.uk.

{dagger} Present address: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom.

Molecular and Cellular Biology, June 2002, p. 3577-3589, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3577-3589.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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