Epigallocatechin-3-Gallate Prevents Autoimmune-Associated Down- Regulation of p21 in Salivary Gland Cells Through a p53-Independent Pathway
Douglas Dickinson, Hongfang Yu, Seiji Ohno, Cristina Thomas, Scott DeRossi, Yat-Ho Ma, Nicole Yates, Emily Hahn, Frederick Bisch, Tetsuya Yamamoto and Stephen Hsu
Affiliation: AD1443 College of Dental Medicine, Georgia Regents University, 1120 15th Street, Augusta, GA 30912, USA.
Keywords: Autoimmune disease, EGCG, non-obese diabetic mouse, p21, p53, PCNA, salivary gland.
The submandibular salivary glands of non-obese diabetic (NOD) mice, a model for Sjogren’s syndrome and
type-1 diabetes, show an elevated level of proliferating cell nuclear antigen (PCNA), a protein involved in cell
proliferation and repair of DNA damage. We reported previously that epigallocatechin-3-gallate (EGCG), the most
abundant green tea catechin, normalizes the PCNA level. PCNA’s activity can be regulated by the cyclin-dependent
kinase inhibitor p21, which is also important for epithelial cell differentiation. In turn, expression of p21 and PCNA are
partially regulated by Rb phosphorylation levels. EGCG was found to modulate p21 expression in epithelial cells,
suggesting that EGCG-induced p21 could be associated with down-regulation of PCNA in vivo. The current study
examined the protein levels of p21 and p53 (which can up-regulate p21) in NOD mice fed with either water or EGCG, and
the effect of EGCG on p21 and p53 in cell line models with either normal or defective Rb. In NOD mice, the p21 level
was low, and EGCG normalized it. In contrast to HSG cells with functional Rb, negligible expression of p21 in NS-SVAC
cells that lack Rb was not altered by EGCG treatment. Inhibition of p53 by siRNA demonstrated that p21 and p53
were induced independently in HSG cells by a physiological concentration range of EGCG, suggesting p53 could be an
important but not conditional factor associated with p21 expression. In conclusion, PCNA and p21 levels are altered
inversely in the NOD model for SS and in HSG cells, and warrant further study as candidate new markers for salivary
dysfunction associated with xerostomia. Induction of p21 by EGCG could provide clinically useful normalization of
salivary glands by promoting differentiation and reducing PCNA levels.
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