Tankyrase, which functions at telomeres and other cellular compartments, is thought to be a positive regulator of telomerase; its isoenzyme tankyrase 2 has been cloned as a putative cancer antigen. This pilot immunohistochemical study was designed to examine whether tumors overexpress tankyrase 2. An antibody was generated by using synthetic peptide specific for tankyrase 2 and was tested by Western blot and immunocytochemically; no cross-reaction with isoenzyme 1 was revealed. Among tissue sections, two tumors of 18 specimens were positive for tankyrase 2. Others were negative or contained barely detectable protein. The surrounding normal tissues were negative. Tankyrase 2 was also revealed in epithelial cells of a limited number of normal renal tubules, whereas other renal tissues were negative. These data suggest that tankyrase 2 is not expressed ubiquitously in human tissues. To determine whether the up-regulation of tankyrase 2 is associated with tissue regeneration and cell proliferation, we compared the activity and concentration of the enzyme in a model human embryonic kidney cell line 293 arrested by serum deprivation and restimulated with serum. The serum-starved quiescent cell culture exhibited detectable protein as did the proliferating cells; enzyme activity dramatically increased in the latter. We conclude that pathologic overexpression of tankyrase 2 in some tumors may be a result of the cancer-related adaptation of the malignant cells dependent on tankyrase activity. Under normal conditions, the protein might be up-regulated during cell differentiation and also posttranslationally in proliferating cells.