التفاصيل البيبلوغرافية
| العنوان: |
E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells. |
| المؤلفون: |
Won Dong Kim, Young Woo Kim, Il Je Cho, Chang Ho Lee, Sang Geon Kim |
| المصدر: |
Journal of Cell Science; 3/1/2012, Vol. 125 Issue 5, p1284-1295, 12p |
| مصطلحات موضوعية: |
CADHERINS, CANCER cells, PHOSPHORYLATION, UBIQUITINATION, ALANINE |
| مستخلص: |
Nrf2 has an anti-carcinogenic effect. However, an increase in Nrf2 activity is also implicated in cancer chemoresistance. A switch from E-cadherin to N-cadherin affects the transdifferentiation and metastasis of cancer cells. In view of the key role of this switch in cancer malignancy, we investigated the regulatory effect of E-cadherin on Nrf2. In HEK293 cells, overexpression of E-cadherin inhibited the nuclear accumulation of Nrf2, and prevented Nrf2-dependent gene induction. GST pull-down and immunocytochemical assays verified the interaction between E-cadherin and Nrf2: E-cadherin bound the C-terminus of Nrf2, but not its N-terminus, which comprises the Neh2 domain responsible for phosphorylation of Ser40. Our finding that the mutation of Ser40 to alanine in Nrf2 did not affect the ability of E-cadherin to bind Nrf2 and repress target gene transactivation suggests that E-cadherin might not disturb the phosphorylation. Studies using mutant constructs of E-cadherin suggested that the β-catenin-binding domain contributes to the inhibitory effect of Ecadherin on Nrf2. Consistently, knockdown of β-catenin attenuated not only the effect of E-cadherin binding to Nrf2, but also Keap1- dependent ubiquitylation of Nrf2, and thereby increased Nrf2 activity, supporting the involvement of b-catenin in the interactions. Collectively, E-cadherin recruits Nrf2 through β-catenin, and assists the function of Keap1 for the inhibition of nuclear localization and transcriptional activity of Nrf2. In HepG2 cells, the loss of E-cadherin by either siRNA knockdown or treatment with TGFb1 enhanced the constitutive or inducible activity of Nrf2, implying that chemoresistance of cancer cells upon the loss of E-cadherin might be associated with Nrf2. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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