Molecular Cell
Volume 14, Issue 2, 23 April 2004, Pages 207-219
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Article
A Cathepsin L Isoform that Is Devoid of a Signal Peptide Localizes to the Nucleus in S Phase and Processes the CDP/Cux Transcription Factor

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Abstract

The subclass of cysteine proteases termed lysosomal cathepsins has long been thought to be primarily involved in end-stage protein breakdown within lysosomal compartments. Furthermore, few specific protein substrates for these proteases have been identified. We show here that cathepsin L functions in the regulation of cell cycle progression through proteolytic processing of the CDP/Cux transcription factor. CDP/Cux processing in situ was increased following ectopic expression of cathepsin L but was reduced in Cat L−/− cells. Furthermore, catalytically active cathepsin L was localized to the nucleus during the G1-S transition as detected by immunofluorescence imaging and labeling using activity-based probes. Trafficking of cathepsin L to the nucleus is accomplished through a mechanism involving translation initiation at downstream AUG sites and the synthesis of proteases that are devoid of a signal peptide. Overall, these results uncover an as yet unsuspected role for cysteine proteases in the control of cell cycle progression.

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7

These authors contributed equally to this work.

10

Present address: Celera Genomics, 180 Kimball Way, South San Francisco, California 94080.

8

Present address: Massachusetts General Hospital, Cancer Center, 13th Street, Charlestown, Massachusetts 02129.

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Present address: Department of Pathology, Stanford Medical School, 300 Pasteur Drive, Stanford, California 94305.