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(American Journal of Pathology. 2003;163:1395-1404.)
© 2003 American Society for Investigative Pathology

Down-Regulation of a Novel Actin-Binding Molecule, Skeletrophin, in Malignant Melanoma

Tamotsu Takeuchi^*, Henry H. Q. Heng, Christine J. Ye, Sheng-Ben Liang, Jun Iwata, Hiroshi Sonobe^¶ and Yuji Ohtsuki^*

From the Department of Pathology,^* Kochi Medical School, Kochi, Japan; SeeDNA Biotech Inc., Ontario, Canada; the Division of Experimental Therapeutics, Ontario Cancer Institute, Toronto, Canada; the Department of Laboratory Investigation, Kochi Municipal Central Hospital, Kochi, Japan; and the Department of Laboratory Medicine and Pathology,^¶ National Fukuyama Hospital, Hiroshima, Japan

In the present study, we cloned and characterized a novel actin-binding molecule, designated skeletrophin, from aggregated neuroblastoma cells. The putative amino acid sequence of human skeletrophin cDNA contained a cysteine-rich zinc-finger motif which was also found in dystrophin and five ankyrin repeats. Northern blot analysis revealed that the 3.2-kb skeletrophin mRNA was expressed in normal skeletal muscle, and to a lesser extent in heart, brain, and kidney. Specific antibody was prepared to human skeletrophin peptide, and a single protein band with an approximate molecular weight of 70 kd was detected in tissue extracts by immunoblotting using the antibody. To better understand the biological properties of skeletrophin, we used a yeast two-hybrid system to screen for molecules interacting with skeletrophin and found that skeletrophin bound to actin monomer. Co-immunoprecipitation experiments also demonstrated that skeletrophin was able to bind to actin monomer. Fluorescence in situ hybridization mapped the skeletrophin gene on human chromosome 1p36.2–36.3, in which putative tumor suppressor genes for malignant melanoma have been postulated to exist. We therefore immunohistochemically stained benign nevi and malignant melanoma tissues. Notably, 23 of 25 benign nevi expressed skeletrophin in cytoplasm, but 18 of 38 cases of primary skin melanoma appeared to lack skeletrophin expression. Treatment with a demethylating agent, 5'-aza-2-deoxycytidine, restored skeletrophin expression in cultured Mewo melanoma cells. The present findings suggest that skeletrophin may be a novel actin-binding cytoskeleton-related molecule, expression of which is silenced in a considerable number of melanoma specimens.

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