Loss of giant obscurins promotes breast epithelial cell survival through apoptotic resistance.
FASEB J
; 26(7): 2764-75, 2012 Jul.
Article
en En
| MEDLINE
| ID: mdl-22441987
ABSTRACT
Obscurins (â¼70 - 870 kDa), encoded by the single OBSCN gene, are cytoskeletal proteins originally identified in striated muscles with structural and regulatory roles. Recently, analysis of 13,023 genes in breast and colorectal cancers identified OBSCN as one of the most frequently mutated genes, implicating it in cancer formation. Herein we studied the expression profile of obscurins in breast, colon, and skin cancer cell lines and their involvement in cell survival. Immunoblot analysis demonstrated significant reduction of obscurin proteins [corrected] in cancer cells, resulting from decreased mRNA levels and/or the presence of mutant transcripts. In normal epithelium, obscurins localize in cytoplasmic puncta, the cell membrane, and the nucleus. Accordingly, subcellular fractionation demonstrated the presence of 2 novel nuclear isoforms of â¼110 and â¼120 kDa. Nontumorigenic MCF10A breast epithelial cells stably transduced with shRNAs targeting giant obscurins exhibited increased viability (â¼30%) and reduced apoptosis (â¼20%) following exposure to the DNA-damaging agent etoposide. Quantitative RT-PCR further indicated that the antiapoptotic genes BAG4 and HAX1 were up-regulated (1.5- and 1.4-fold, respectively), whereas initiator caspase-9 and death caspase-3 transcripts were down-regulated (0.8- and 0.6-fold, respectively). Our findings are the first to pinpoint critical roles for obscurins in cancer development by contributing to the regulation of cell survival.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Mama
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Factores de Intercambio de Guanina Nucleótido
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Proteínas Musculares
Idioma:
En
Revista:
FASEB J
Asunto de la revista:
BIOLOGIA
/
FISIOLOGIA
Año:
2012
Tipo del documento:
Article