The human non-muscle alpha-actinin protein encoded by the ACTN4 gene suppresses tumorigenicity of human neuroblastoma cells

alpha-Actinins are actin-binding proteins important in organization of the cytoskeleton and in cell adhesion. We have cloned and characterized a cDNA from human neuroblastoma cell variants which encodes the second non-muscle alpha-actinin isoform designated ACTN4 (actinin-4), mRNA encoded by the ACT N4 gene, mapped to chromosome 4, is abundant in non-tumorigenic, substrate- adherent human neuroblastoma cell variants but absent or only weakly expres sed in malignant, poorly substrate-adherent neuroblasts, It is also present in many adherent tumor cell lines of diverse tissue origins. Cell lines ty pically co-express ACTN4 and ACTN1, a second non-muscle alpha-actinin gene. Expression is correlated with substrate adhesivity, Analysis of deduced am ino acid sequences suggests that the two isoforms may differ in function an d in regulation by calcium. Moreover, ACTN4 exhibits tumor suppressor activ ity. Stable clones containing increased levels of alpha-actinin, isolated f rom highly malignant neuroblastoma stem cells [BE(2)-C] after transfection with a full-length ACTN4 cDNA, show decreased anchorage-independent growth ability, loss of tumorigenicity in nude mice, and decreased expression of t he N-myc proto-oncogene.