Abstract
The TRP73 gene, a member of the p53 family, encodes several variants through differential splicing and use of alternative promoters. At the N terminus, two different promoters generate the full-length and the DeltaN isoforms, with or without the transactivating domain. At the C terminus, seven isoforms generated through alternative splicing have been cloned. Previous studies have demonstrated that DeltaN-p73 interferes with p73-induced apoptosis. However, there has been no evidence for functional diversity of the C-terminal p73 variants. In this study, we found that p73alpha and p73beta exerted differential effect on the differentiation of C2C12 myoblasts. Although p73beta lacked any detectable effect on differentiation, p73alpha caused a substantial delay in the expression of muscle-specific genes. In co-transfection experiments p73alpha, but not p73beta, attenuated the transcriptional activity of MyoD. Microarray-based gene profiling confirmed the protraction of MyoD-dependent gene expression in C2C12 cells stably expressing p73alpha. Notwithstanding the differential effect on differentiation, p73alpha and p73beta showed similar activity in sensitizing C2C12 myoblasts to cisplatin-induced cell death. These results demonstrated a functional diversity between the two C-terminal variants of p73 and suggested that p73alpha can regulate cellular differentiation in addition to its role in stimulating cell death.
Highlights
The TRP73 gene, a member of the p53 gene family, encodes several variants of the p73 protein
To determine whether this suppression of p73 is relevant to the differentiating potential of C2C12 cells, we examined the consequence of ectopically expressing p73 on myogenic differentiation of C2C12 myoblasts
After 24 h of transfection, the cultures were shifted into differentiation media (DM) to allow the activation of MyoD and the onset of myogenic differentiation [29, 30]
Summary
The TRP73 gene, a member of the p53 gene family, encodes several variants of the p73 protein. At the 5Ј-end of the gene, two alternative promoters drive the expression of N-terminal variants of p73, one of which encodes a transactivation (TA) domain, whereas the other (⌬N) lacks the TA domain. At the 3Ј-end, alternative splicing gives rise to seven different isoforms (denominated ␣, , ␥, ␦, ⑀, , and ) with disparate C-terminal sequences [1, 2] Among these splicing variants, p73␣ contains the longest C-terminal sequence, and it is the predominant p73 isoform expressed in cultured human cell lines [3,4,5,6]. The TA-p73␣ expression is detected in differentiating slow muscle cells of somites and pharyngeal endoderm [27] These observations indicate that p73 may participate in the regulation of development. We found that p73␣, but not p73, suppressed myogenic differentiation, but both isoforms promoted apoptotic response of C2C12 cells to genotoxic stress
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