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14-3-3sigma controls corneal epithelial cell proliferation and differentiation through the Notch signaling pathway.

ABSTRACT: 14-3-3sigma (also called stratifin) is specifically expressed in the stratified squamous epithelium and its function was recently shown to be linked to epidermal stratification and differentiation in the skin. In this study, we investigated its role in corneal epithelium cell proliferation and differentiation. We showed that the 14-3-3sigma mutation in repeated epilation (Er) mutant mice results in a dominant negative truncated protein. Primary corneal epithelial cells expressing the dominant negative protein failed to undergo high calcium-induced cell cycle arrest and differentiation. We further demonstrated that blocking endogenous 14-3-3sigma activity in corneal epithelial cells by overexpressing dominative negative 14-3-3sigma led to reduced Notch activity and Notch1/2 transcription. Significantly, expression of the active Notch intracellular domain overcame the block in epithelial cell differentiation in 14-3-3sigma mutant-expressing corneal epithelial cells. We conclude that 14-3-3sigma is critical for regulating corneal epithelial proliferation and differentiation by regulating Notch signaling activity.

SUBMITTER: Xin Y

PROVIDER: S-EPMC2828677 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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14-3-3sigma controls corneal epithelial cell proliferation and differentiation through the Notch signaling pathway.

Xin Ying Y Lu Qingxian Q Li Qiutang Q

Biochemical and biophysical research communications 20100125 4

14-3-3sigma (also called stratifin) is specifically expressed in the stratified squamous epithelium and its function was recently shown to be linked to epidermal stratification and differentiation in the skin. In this study, we investigated its role in corneal epithelium cell proliferation and differentiation. We showed that the 14-3-3sigma mutation in repeated epilation (Er) mutant mice results in a dominant negative truncated protein. Primary corneal epithelial cells expressing the dominant ne ...[more]

PMID: 20100467

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Project description:BACKGROUND: 14-3-3sigma is a p53-mediated cell-cycle inhibitor in epithelial cells. The expression of 14-3-3sigma is frequently altered in cancers of epithelial origin associated with altered DNA methylation. Since its involvement in a non-epithelial tumor is unknown, we examined 14-3-3sigma expression in patients with haematological malignancies. METHODS: We analyzed 41 hematopoietic cell lines and 129 patients with a variety of hematological malignancies for 14-3-3sigma expression with real-time RT-PCR. We also examined protein levels by Western blot analysis and DNA methylation status of the 14-3-3sigma gene by methylation-specific PCR analysis of bisulfite-treated DNA. In addition, mutations of p53 gene were identified by RT-PCR-SSCP analysis and the expression levels of 14-3-3sigma were compared with those of other cell-cycle inhibitor genes, CDKN2A and ARF. RESULTS: The expression levels of 14-3-3sigma mRNA in almost all cell lines were low and comparable to those in normal hematopoietic cells except for 2 B-cell lines. On the contrary, 14-3-3sigma mRNA was aberrantly overexpressed frequently in mature lymphoid malignancies (30 of 93, 32.3%) and rarely in acute leukemia (3 of 35, 8.6%). 14-3-3sigma protein was readily detectable and roughly reflected the mRNA level. In contrast to epithelial tumors, methylation status of the 14-3-3sigma gene was not associated with expression in hematological malignancies. Mutations of p53 were identified in 12 patients and associated with lower expression of 14-3-3sigma. The expression levels of 14-3-3sigma, CDKN2A and ARF were not correlated with but rather reciprocal to one another, suggesting that simultaneous overexpression of any two of them is incompatible with tumor growth. CONCLUSION: 14-3-3sigma, an epithelial cell marker, was overexpressed significantly in a subset of mature lymphoid malignancies. This is the first report of aberrant 14-3-3sigma expression in non-epithelial tumors in vivo. Since the significance of 14-3-3sigma overexpression is unknown even in epithelial tumors such as pancreatic cancers, further analysis of regulation and function of the 14-3-3sigma gene in non-epithelial as well as epithelial tumors is warranted.

Dataset Information

14-3-3sigma controls corneal epithelial cell proliferation and differentiation through the Notch signaling pathway.

Publications

14-3-3sigma controls corneal epithelial cell proliferation and differentiation through the Notch signaling pathway.

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