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Cloning and Expression Analysis of Human Bleomycin Hydrolase, a Cysteine Proteinase Involved in Chemotherapy Resistance¹

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo [A. A. F., G. V., C. L-O.], and Departamento de Anatomía Patológica, Hospital Clínico-Barcelona and Facultad de Medicina, Universidad de Lérida, 25006 Lérida [E. C.] Spain

A cDNA encoding human bleomycin hydrolase, a member of the cysteine proteinase family of proteins, has been cloned from a human brain cDNA library. The isolated cDNA contains an open reading frame coding for a polypeptide of 456 amino acids that contains all of the structural features characteristic of cysteine proteinases, including the cysteine, histidine, and asparagine residues that are essential for the catalytic properties of these enzymes. The deduced amino acid sequence for human bleomycin hydrolase shows 92, 40, and about 35% of identities with those determined for rabbit bleomycin hydrolase, yeast bleomycin hydrolase, and bacterial aminopeptidase C, respectively. Northern blot analysis of poly(A)⁺ RNAs isolated from a variety of human tissues demonstrated that human bleomycin hydrolase is expressed in all examined tissues, which is consistent with a putative role of this protein as a proteolytic enzyme involved in normal cellular protein degradation and turnover. Preliminary expression analysis of bleomycin hydrolase in different human tumors showed increased expression of the enzyme in a series of head and neck carcinomas when compared with paired adjacent normal mucosa. We also observed a variable degree of bleomycin hydrolase expression in different types of lymphoma, with low or undetectable levels in Hodgkin's disease samples and higher levels in Burkitt's lymphomas. These results are consistent with a proposed role for human bleomycin hydrolase in resistance of some tumors to bleomycin chemotherapy.

¹ This work was supported by Grants SAF94-0892 and SAF93-1195 from the Comisión Interministerial de Ciencia y Tecnología. A. A. F is a recipient of the "Severo Ochoa" fellowship from Ayuntamiento de Oviedo-Asturias (Spain).

² To whom requests for reprints should be addressed. Phone: 34-85-104201; Fax: 34-85-103564.

Received 1/18/96. Accepted 3/ 1/96.

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