Estrogen receptor a (ERA) is a DNA-binding transcription factor that plays an important role in the regulation of cell growth. Previous studies indicated that the expression of ERa in cell lines and tumors derived from oral squamous cell carcinoma (OSCC). The aim of this study was to examine the activity and function of ERa in OSCC cells and the mechanism underlying ERa activation. Immunochemical analyses in benign (nZ11) and malignant (nZ21) lesions of the oral cavity showed that ERa immunoreactivity was observed in 43% (9/21) of malignant lesions, whereas none of benign lesions showed ERa immunoreactivity. The ERa expression was also found in three OSCC cell lines and its transcriptional activity was correlated with cell growth. Addition of estradiol stimulated cell growth, whereas treatment of tamoxifen or knockdown of ERa expression caused reduced cell growth. Interestingly, the expression and activity of focal adhesion kinase (FAK) were associated with the phosphorylation of ERa at serine 118 in OSCC cells. Elevated expression of FAK in the slow-growing SCC25 cells caused increases in ERa phosphorylation, transcriptional activity, and cell growth rate, whereas knockdown of FAK expression in the rapid-growing OECM-1 cells led to reduced ERa phosphorylation and activity and retarded cell growth. Inhibition of the activity of protein kinase B (AKT), but not ERK, abolished FAK-promoted ERa phosphorylation. These results suggest that OSCC cells expressed functional ERa, whose activity can be enhanced by FAK/AKT signaling, and this was critical for promoting cell growth. Thus, FAK and ERa can serve as the therapeutic targets for the treatment of OSCC. Key Words" oral squamous cell carcinoma " estrogen receptor a " focal adhesion kinase

The Arabidopsis thaliana T-DNA insertion mutant glucose hypersensitive (ghs) 40-1 exhibited hypersensitivity to glucose (Glc) and abscisic acid (ABA). The ghs40-1 mutant displayed severely impaired cotyledon greening and expansion and showed enhanced reduction in hypocotyl elongation of dark-grown seedlings when grown in Glc concentrations higher than 3 %. The Glc-hypersensitivity of ghs40-1 was correlated with the hyposensitive phenotype of 35S::AtGHS40 seedlings. The phenotypes of ghs40-1 were recovered by complementation with 35S::AtGHS40. The AtGHS40 (At5g11240) gene encodes a WD40 protein localized primarily in the nucleus and nucleolus using transient expression of AtGHS40-mRFP in onion cells and of AtGHS40-EGFP and EGFP-AtGHS40 in Arabidopsis protoplasts. The ABA biosynthesis inhibitor fluridone extensively rescued Glc-mediated growth arrest. Quantitative real time-PCR analysis showed that AtGHS40 was involved in the control of Glc-responsive genes. AtGHS40 acts downstream of HXK1 and is activated by ABI4 while ABI4 expression is negatively modulated by AtGHS40 in the Glc signaling network. However, AtGHS40 may not affect ABI1 and SnRK2.6 gene expression. Given that AtGHS40 inhibited ABA degrading and signaling gene expression levels under high Glc conditions, a new circuit of fine-tuning modulation by which ABA and ABA signaling gene expression are modulated in balance, occurred in plants. Thus, AtGHS40 may play a role in ABA-mediated Glc signaling during early seedling development. The biochemical function of AtGHS40 is also discussed.

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