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, Stephen Hsu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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-SV-AC 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.

Original languageEnglish (US)
Pages (from-to)15-24
Number of pages10
JournalInflammation and Allergy - Drug Targets
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Salivary Glands
Proliferating Cell Nuclear Antigen
Down-Regulation
Inbred NOD Mouse
Epithelial Cells
Cyclin-Dependent Kinase Inhibitor p21
epigallocatechin gallate
Xerostomia
Catechin
Submandibular Gland
Sjogren's Syndrome
Tea
Type 1 Diabetes Mellitus
Small Interfering RNA
DNA Damage
Cell Differentiation
Proteins
Up-Regulation
Phosphorylation
Cell Proliferation

Keywords

  • Autoimmune disease
  • EGCG
  • Non-obese diabetic mouse
  • P21
  • P53
  • PCNA
  • Salivary gland

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Epigallocatechin-3-gallate prevents autoimmune-associated down-regulation of p21 in salivary gland cells through a p53-independent pathway. / Dickinson, Douglas; Yu, Hongfang; Ohno, Seiji; Thomas, Cristina; DeRossi, Scott; Ma, Yat Ho; Yates, Nicole; Hahn, Emily; Bisch, Frederick; Yamamoto, Tetsuya; Hsu, Stephen.

In: Inflammation and Allergy - Drug Targets, Vol. 13, No. 1, 01.01.2014, p. 15-24.

Research output: Contribution to journalArticle

Dickinson, Douglas ; Yu, Hongfang ; Ohno, Seiji ; Thomas, Cristina ; DeRossi, Scott ; Ma, Yat Ho ; Yates, Nicole ; Hahn, Emily ; Bisch, Frederick ; Yamamoto, Tetsuya ; Hsu, Stephen. / Epigallocatechin-3-gallate prevents autoimmune-associated down-regulation of p21 in salivary gland cells through a p53-independent pathway. In: Inflammation and Allergy - Drug Targets. 2014 ; Vol. 13, No. 1. pp. 15-24.
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abstract = "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-SV-AC 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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AU - Thomas, Cristina

AU - DeRossi, Scott

AU - Ma, Yat Ho

AU - Yates, Nicole

AU - Hahn, Emily

AU - Bisch, Frederick

AU - Yamamoto, Tetsuya

AU - Hsu, Stephen

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AB - 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-SV-AC 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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