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Int J Clin Exp Pathol. 2014 Aug 15;7(9):5515-26. eCollection 2014.

Ectopic expression of new alternative splice variant of Smac/DIABLO increases mammospheres formation.

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Functional Cancer Genomics Laboratory, National Institute of Genomic Medicine Periférico Sur 4809, Col. Arenal Tepepan, Tlalpan 14610, Mexico.


Smac-α is a mitochondrial protein that, during apoptosis, is translocated to the cytoplasm, where it negatively regulates members of the inhibitor of apoptosis (IAP) family via the IAP-binding motif (IBM) contained within its amino-terminus. Here, we describe a new alternative splice variant from Smac gene, which we have named Smac-ε. Smac-ε lacks both an IBM and a mitochondrial-targeting signal (MTS) element. Smac-ε mRNA exhibits a tissue-specific expression pattern in healthy human tissues as well as in several cancer cell lines. The steady-state levels of endogenous Smac-ε protein is regulated by the proteasomal pathway. When ectopically expressed, this isoform presents a cytosolic localization and is unable to associate with or to regulate the expression of X-linked Inhibitor of apoptosis protein, the best-studied member of IAP family. Nevertheless, over-expression of Smac-ε increases mammosphere formation. Whole genome expression analyses from these mammospheres show activation of several pro-survival and growth pathways, including Estrogen-Receptor signaling. In conclusion, our results support the functionality of this new Smac isoform.


Smac-ε; breast; cancer; tumorigenicity

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