ABSTRACT
Skeletal myogenesis is an intricate process coordinated temporally by multiple myogenic regulatory factors (MRF) including Myf5, which is the first MRF expressed and marks the commitment of skeletal muscle lineage. The expression of Myf5 gene during early embryogenesis is controlled by a set of enhancer elements, and requires the histone acetyltransferase (HAT) activity of transcriptional coactivator p300. However, it is unclear as to how different regulatory signals converge at enhancer elements to regulate early Myf5 gene expression, and if p300 is directly involved. We show here that p300 associates with the Myf5 early enhancer at the early stage of stem cell differentiation, and its HAT activity is important for the recruitment of ß-catenin to this early enhancer. In addition, histone H3-K27 acetylation, but not H3-K9/14, is intimately connected to the p300 HAT activity. Thus, p300 is directly involved in the regulation of the Myf5 early enhancer, and is important for specific histone acetylation and transcription factor recruitment. This connection of p300 HAT activity with H3-K27 acetylation and ß-catenin signalling during myogenic differentiation in vitro offers a molecular insight into the enhancer-elements participation observed in embryonic development. In addition, pluripotent stem cell differentiation is a valuable system to dissect the signal-dependent regulation of specific enhancer element during cell fate determinations.
ABSTRACT
Myogenic regulatory factors (MRFs) are the master regulators of skeletal myogenesis. Among the MRFs, Myf5 is the earliest to be expressed and is regulated by a complex set of enhancers. The expression of Myf5 defines different muscle populations in the somite. Furthermore, Myf5 expression is also found in non-muscle tissues, such as preadipocytes and neurons. Here, we present a current view on the regulation of skeletal myogenesis by transcription factors and cellular signals, with an emphasis on the complexity of transcriptional activation of Myf5. We also discuss Myf5 expression in different populations of myoblasts, preadipocytes and neuronal tissue.
ABSTRACT
OBJECTIVE: To determine whether eukaryotic elongation factor 1 alpha 2 (eEF1A2), a transforming gene previously shown to be highly expressed in primary human ovarian tumours, is a prognostic marker. METHODS: We have used an antibody specific for eEF1A2 to measure eEF1A2 protein expression in 500 primary ovarian tumours in a tissue microarray. We have also ectopically expressed eEF1A2 in SK-OV-3 cells, a clear cell carcinoma line that does not normally express eEF1A2. RESULTS: We have shown that eEF1A2 has high expression levels in approximately 30% of all primary ovarian tumours. 50% of serous tumours, 30% of endometrioid, 19% of mucinous and 8% of clear cell tumours highly express eEF1A2. Ectopic expression of eEF1A2 in the SK-OV-3 clear cell carcinoma line enhances their in vitro proliferative capacity and ability to form tumour-like spheroids in hanging drop culture. Expression of eEF1A2 did not alter sensitivity to anoikis, cisplatin, or taxol. In serous cancer, eEF1A2 is an independent prognostic marker for survival and high eEF1A2 protein expression was associated with increased probability of 20-year survival. CONCLUSIONS: eEF1A2 is highly expressed in ovarian carcinomas. Its expression enhances cell growth in vitro, and eEF1A2 expression is likely to be a useful ovarian cancer prognostic factor in ovarian cancer patients with serous tumours.
