HUMAN CARBONIC-ANHYDRASE XII - CDNA CLONING, EXPRESSION, AND CHROMOSOMAL LOCALIZATION OF A CARBONIC-ANHYDRASE GENE THAT IS OVEREXPRESSED INSOME RENAL-CELL CANCERS

We report the cloning and characterization of a tumor-associated carbo nic anhydrase (CA) that was identified in a human renal cell carcinoma (RCC) by serological expression screening with autologous antibodies. The cDNA sequence predicts a 354-amino acid poly-peptide with a molec ular mass of 39,448 Da that has features of a type I membrane protein. The predicted sequence includes a 29-amino acid signal sequence, a 26 1-amino acid CA domain, an additional short extracellular segment, a 2 6-amino acid hydrophobic transmembrane domain, and a hydrophilic C-ter minal cytoplasmic tail of 29 amino acids that contains two potential p hosphorylation sites. The extracellular CA domain shows 30-42% homolog y with known human CAs, contains all three Zn-binding histidine residu es found in active CAs, and contains two potential sites for asparagin e glycosylation. When expressed in COS cells, the cDNA produced a 43- to 44-kDa protein in membranes that had around one-sixth the CA activi ty of membranes from COS cells transfected with the same vector expres sing bovine CA IV. We have designated this human protein CA XII. North ern blot analysis of normal tissues demonstrated a 4.5-kb transcript o nly in kidney and intestine. However, in 10% of patients with RCC, the CA SII transcript was expressed at much higher levels in the RCC than in surrounding normal kidney tissue. The CA XII gene was mapped by us ing fluorescence in situ hybridization to 15q22, CA XII is the second catalytically active membrane Cii reported to be overexpressed in cert ain cancers. Its relationship to oncogenesis and its potential as a cl inically useful tumor marker clearly merit further investigation.