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Signaling and Regulation

Proteolytic Processing of Cut Homeobox 1 by Neutrophil Elastase in the MV4;11 Myeloid Leukemia Cell Line

¹ Molecular Oncology Group, McGill University Health Center and Departments of ² Biochemistry, ³ Medicine, and ⁴ Oncology, McGill University, Montreal, Quebec, Canada

Requests for reprints: Alain Nepveu, Molecular Oncology Group, McGill University Health Center, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Phone: 514-934-1934, ext. 35842; Fax: 514-843-1478. E-mail: alain.nepveu{at}mcgill.ca

Proteolytic processing by cathepsin L generates p110 Cut homeobox 1 (CUX1) at the end of the G₁ phase, whereas an alternative transcript encodes p75 CUX1. These short CUX1 isoforms were reported to be overexpressed in cancer cells, and transgenic mice overexpressing the p75 isoform were found to develop myeloproliferative disease–like myeloid leukemias. In the present study, we report that the neutrophil elastase can also generate a short CUX1 isoform in the MV4;11 acute myeloid leukemia cell line. Proteolytic processing was so efficient that the full-length CUX1 protein was detected only when cells were maintained in the presence of the specific elastase inhibitor III. In agreement with these findings, higher levels of the processed cyclin E isoforms were also detected in MV4;11 cells. Reappearance of full-length cyclin E and CUX1 could be induced upon the treatment of MV4;11 cells with the differentiation inducer phorbol 12-myristate 13-acetate or, unexpectedly, following overexpression of a short recombinant CUX1 protein. In both cases, the mechanism involved transcriptional repression of the neutrophil elastase gene. This result revealed a negative feedback loop whereby CUX1 shuts down the expression of the protease that cleaves it. Overall, the findings in MV4;11 and other cancer cells suggest that various mechanisms are used in cancer to favor the expression of short CUX1 isoforms. (Mol Cancer Res 2008;6(4):644–53)