While the majority of RNA transcripts from protein-encoding genes in the human 
genome are subject to physiological splicing, pathological splicing is 
increasingly reported in cancer tissue. Previously, we identified >90 different 
splice variants of Chk2, a gene encoding a serine/threonine kinase propagating 
the DNA damage signal by phosphorylating and activating several downstream 
substrates like p53, Cdc25A, and Cdc25C involved in cell cycle arrest and 
apoptosis. While alternative splice forms of other genes have been reported to 
exert a dominant-negative effect on the wild-type molecules, the function of 
Chk2 splice protein variants is still unclear. Here we evaluated the function of 
four Chk2 splice proteins for which mRNA splice variants were identified in 
human breast carcinomas. These splice variants were stably expressed as nuclear 
proteins. Two splice forms (Chk2Delta4 and Chk2del(2-3)) expressed kinase 
activity while variants Chk2Delta11 and Chk2isoI were essentially kinase 
inactive. Independent of intrinsic kinase activity, each splice variant impaired 
wild-type Chk2 activity through heterodimerization. Based on our findings, we 
suggest alternative splicing as a possible novel mechanism for repression of the 
Chk2 wild-type function.