SYNTHESIS AND FUNCTION OF A TRANSFORMATION-DEPENDENT SECRETED LYSOSOMAL PROTEASE

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Procathepsin L (also known as MEP, for major excreted protein) is a lysosomal protease which is synthesized and secreted in large amounts by malignantly transformed mouse and human cells, as well as by normal cells of the kidney and liver. Cathepsin L is a cysteine acid protease with a broad substrate specificity which includes many extracellular matrix substrates. To understand the mode of regulation of cathepsin L, we have isolated both the mouse and human genes and studied their upstream, promoter regions. The mouse promoter has elements both 5' and 3' to the start site of transcription which affect regulation by the tumor promoter, TPA. The human gene, which maps to chromosome 9, appears to have two distinct promoters which determine expression of two transcripts in most human tissues. A deletion analysis of a full-length human procathepsin L cDNA expressed in cultured mouse cells has revealed many features of the protein involved in subcellular localization and function. Sequences in the amino terminal section of the protein appear to be involved in protein folding and their deletion results in trapping of procathepsin L in the endoplasmic reticulum. Amino acid residues at the carboxy terminal end of cathepsin L affect its ability to be secreted.