Two COOH-Terminal Truncated Cytoplasmic Forms of Topoisomerase IIα in a VP-16-Selected Lung Cancer Cell Line Result from Partial Gene Deletion and Alternative Splicing†

Topoisomerase IIα is a nuclear enzyme involved in chromosome segregation and other essential cellular processes. It is also the target of several clinically important antineoplastic agents such as the epipodophyllotoxin, VP-16 (etoposide). We have previously described a VP-16-selected lung cancer cell line, H209/V6, that expresses reduced levels of two species of topoisomerase IIα-related mRNAs and a catalytically active, predominantly cytoplasmic topoisomerase IIα-related protein that is 10 kDa smaller than the wild-type protein [Mirski, S. E. L., et al. (1993) Cancer Res. 53, 4866−4873; Feldhoff, P. W. et al. (1994) Cancer Res. 54, 756−762]. The smaller H209/V6 4.8 kb mRNA is missing 988 nucleotides of contiguous coding and non-coding sequence at its 3‘ end resulting in an mRNA predicted to encode a truncated polypeptide missing three previously unrecognized potential COOH-proximal bipartite nuclear localization signals [Mirski, S. E. L., & Cole, S. P. C. (1995) Cancer Res. 55, 2129−2134]. We have now d...