TY - JOUR
T1 - The role of cadherin, β-catenin, and AP-1 in retinoid-regulated carcinoma cell differentiation and proliferation
AU - Shah, Salimuddin
AU - Pishvaian, Michael J.
AU - Easwaran, Vijayasurian
AU - Brown, Powell H.
AU - Byers, Stephen W.
PY - 2002/7/12
Y1 - 2002/7/12
N2 - Vitamin A derivatives (retinoids) are potent regulators of cell proliferation and differentiation. Retinoids inhibit the function of the oncogenic AP-1 and β-catenin/TCF pathways and also stabilize components of the adherens junction, a tumor suppressor complex. When treated with retinoic acid (RA), the breast cancer cell line, SKBR3, undergoes differentiation and reduction in cell proliferation. The present work demonstrates that in SKBR3 cells, which exhibit high AP-1 activity, RA-regulation of cadherin expression and function, but not changes in AP-1 (or β-catenin/TCF) signaling, is responsible for the epithelial differentiation. However, cadherin function and recruitment of β-catenin to the membrane is not required for RA to regulate DNA synthesis in these cells. RA also reduces the activity of an AP-1 and TCF-sensitive cyclin D1 reporter in SKBR3 cells in a manner that is independent of the TCF site. In contrast, in SW480 cells, which have high levels of β-catenin/TCF signaling, the activity and retinoid responsiveness of the cyclin D1 promoter was markedly inhibited by mutation of the TCF site. These data indicate that the remarkably broad effects of RA on the growth and differentiation of many different epithelial cancers may well be explained by the ability of RA to differentially regulate the activity of RAR/RXR, AP-1, and β-catenin/TCF pathways.
AB - Vitamin A derivatives (retinoids) are potent regulators of cell proliferation and differentiation. Retinoids inhibit the function of the oncogenic AP-1 and β-catenin/TCF pathways and also stabilize components of the adherens junction, a tumor suppressor complex. When treated with retinoic acid (RA), the breast cancer cell line, SKBR3, undergoes differentiation and reduction in cell proliferation. The present work demonstrates that in SKBR3 cells, which exhibit high AP-1 activity, RA-regulation of cadherin expression and function, but not changes in AP-1 (or β-catenin/TCF) signaling, is responsible for the epithelial differentiation. However, cadherin function and recruitment of β-catenin to the membrane is not required for RA to regulate DNA synthesis in these cells. RA also reduces the activity of an AP-1 and TCF-sensitive cyclin D1 reporter in SKBR3 cells in a manner that is independent of the TCF site. In contrast, in SW480 cells, which have high levels of β-catenin/TCF signaling, the activity and retinoid responsiveness of the cyclin D1 promoter was markedly inhibited by mutation of the TCF site. These data indicate that the remarkably broad effects of RA on the growth and differentiation of many different epithelial cancers may well be explained by the ability of RA to differentially regulate the activity of RAR/RXR, AP-1, and β-catenin/TCF pathways.
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U2 - 10.1074/jbc.M203158200
DO - 10.1074/jbc.M203158200
M3 - Article
C2 - 12000762
AN - SCOPUS:0037067667
SN - 0021-9258
VL - 277
SP - 25313
EP - 25322
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 28
ER -