scholarly journals Impaired Retinoic Acid (RA) Signal Leads to RARβ2 Epigenetic Silencing and RA Resistance

2005 ◽  
Vol 25 (23) ◽  
pp. 10591-10603 ◽  
Author(s):  
MingQiang Ren ◽  
Silvia Pozzi ◽  
Gaia Bistulfi ◽  
Giulia Somenzi ◽  
Stefano Rossetti ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Inhibitory Action ◽  
Retinoic Acid Receptor ◽  
Suppressor Gene ◽  
Inhibitory Effect ◽  
Dominant Negative ◽  
Growth Inhibitory Effect ◽  
Dynamic Changes ◽  
Growth Inhibitory ◽  
Retinoic Acid Receptor Β2

ABSTRACT Resistance to the growth-inhibitory action of retinoic acid (RA), the bioactive derivative of vitamin A, is common in human tumors. One form of RA resistance has been associated with silencing and hypermethylation of the retinoic acid receptor β2 gene (RARβ2), an RA-regulated tumor suppressor gene. The presence of an epigenetically silent RARβ2 correlates with lack of the RA receptor α (RARα). Normally, RARα regulates RARβ2 transcription by mediating dynamic changes of RARβ2 chromatin in the presence and absence of RA. Here we show that interfering with RA signal through RARα (which was achieved by use of a dominant-negative RARα, by downregulation of RARα by RNA interference, and by use of RARα antagonists) induces an exacerbation of the repressed chromatin status of RARβ2 and leads to RARβ2 transcriptional silencing. Further, we demonstrate that RARβ2 silencing causes resistance to the growth-inhibitory effect of RA. Apparently, RARβ2 silencing can also occur in the absence of DNA methylation. Conversely, we demonstrate that restoration of RA signal at a silent RARβ2 through RARα leads to RARβ2 reactivation. This report provides proof of principle that RARβ2 silencing and RA resistance are consequent to an impaired integration of RA signal at RARβ2 chromatin.

Retinoic Acid Prevents Phosphorylation of pRB in Normal Human B Lymphocytes: Regulation of Cyclin E, Cyclin A, and p21Cip1

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1348-1358 ◽  
Author(s):  
Soheil Naderi ◽  
Heidi Kiil Blomhoff
Keyword(s):  
Retinoic Acid ◽  
B Lymphocytes ◽  
Retinoic Acid Receptor ◽  
Cyclin E ◽  
Cyclin A ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
Normal Human

The mechanisms underlying the growth-inhibitory effect of retinoids on normal human B lymphocytes are not well understood. We addressed this issue by examining the effect of retinoic acid on the cell cycle machinery involved in G1/S transition. When retinoic acid was administered to B cells stimulated into mid to late G1 by anti-IgM antibodies (anti-μ) and Staphylococcus aureus crude cell suspension (SAC), the phosphorylation of pRB required for S-phase entry was prevented in a time- and dose-dependent manner. Thus, 2-hour treatment with retinoic acid at the optimal concentration of 1 μmol/L prevented phosphorylation of pRB, and effects were noted at concentrations as low as 10 nmol/L. Based on our results, we suggest that the rapid effect of retinoic acid on pRB phosphorylation is due primarily to the reduced expression of cyclin E and cyclin A in late G1. This could lead to the diminished cyclin E– and cyclin A–associated kinase activities noted as early as 2 hours after addition of retinoic acid. Furthermore, our results imply that the transient induction of p21Cip1 could also be involved. Thus, retinoic acid induced a rapid, but transient increased binding of p21Cip1 to CDK2. The retinoic acid receptor (RAR) agonist TTNPB mimicked the key events affected by retinoic acid, such as pRB phosphorylation, cyclin E expression, and expression of p21Cip1, whereas the RAR-selective antagonist Ro 41-5253 counteracted the effects of retinoic acid. This implies that retinoic acid mediates its growth-inhibitory effect on B lymphocytes via the nuclear receptors.

Retinoic Acid Prevents Phosphorylation of pRB in Normal Human B Lymphocytes: Regulation of Cyclin E, Cyclin A, and p21Cip1

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1348-1358 ◽  
Author(s):  
Soheil Naderi ◽  
Heidi Kiil Blomhoff
Keyword(s):  
Retinoic Acid ◽  
B Lymphocytes ◽  
Retinoic Acid Receptor ◽  
Cyclin E ◽  
Cyclin A ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Growth Inhibitory Effect ◽  
Growth Inhibitory ◽  
Normal Human

Abstract The mechanisms underlying the growth-inhibitory effect of retinoids on normal human B lymphocytes are not well understood. We addressed this issue by examining the effect of retinoic acid on the cell cycle machinery involved in G1/S transition. When retinoic acid was administered to B cells stimulated into mid to late G1 by anti-IgM antibodies (anti-μ) and Staphylococcus aureus crude cell suspension (SAC), the phosphorylation of pRB required for S-phase entry was prevented in a time- and dose-dependent manner. Thus, 2-hour treatment with retinoic acid at the optimal concentration of 1 μmol/L prevented phosphorylation of pRB, and effects were noted at concentrations as low as 10 nmol/L. Based on our results, we suggest that the rapid effect of retinoic acid on pRB phosphorylation is due primarily to the reduced expression of cyclin E and cyclin A in late G1. This could lead to the diminished cyclin E– and cyclin A–associated kinase activities noted as early as 2 hours after addition of retinoic acid. Furthermore, our results imply that the transient induction of p21Cip1 could also be involved. Thus, retinoic acid induced a rapid, but transient increased binding of p21Cip1 to CDK2. The retinoic acid receptor (RAR) agonist TTNPB mimicked the key events affected by retinoic acid, such as pRB phosphorylation, cyclin E expression, and expression of p21Cip1, whereas the RAR-selective antagonist Ro 41-5253 counteracted the effects of retinoic acid. This implies that retinoic acid mediates its growth-inhibitory effect on B lymphocytes via the nuclear receptors.

scholarly journals Retinoic acid receptor beta mediates the growth-inhibitory effect of retinoic acid by promoting apoptosis in human breast cancer cells.

1996 ◽  
Vol 16 (3) ◽  
pp. 1138-1149 ◽  
Author(s):  
Y Liu ◽  
M O Lee ◽  
H G Wang ◽  
Y Li ◽  
Y Hashimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Retinoic Acid ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Retinoic Acid Receptor ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Differential Growth ◽  
Growth Inhibitory

Retinoids are known to inhibit the growth of hormone-dependent but not that of hormone-independent breast cancer cells. We investigated the involvement of retinoic acid (RA) receptors (RARs) in the differential growth-inhibitory effects of retinoids and the underlying mechanism. Our data demonstrate that induction of RAR beta by RA correlates with the growth-inhibitory effect of retinoids. The hormone-independent cells acquired RA sensitivity when the RAR beta expression vector was introduced and expressed in the cells. In addition, RA sensitivity of hormone-dependent cells was inhibited by a RAR beta-selective antagonist and the expression of RAR beta antisense RNA. Introduction of RAR alpha also restored RA sensitivity in hormone-independent cells, but this restoration was accomplished by the induction of endogenous RAR beta expression. Furthermore, we show that induction of apoptosis contributes to the growth-inhibitory effect of RAR beta. Thus, RAR beta can mediate retinoid action in breast cancer cells by promoting apoptosis. Loss of RAR beta, therefore, may contribute to the tumorigenicity of human mammary epithelial cells.

scholarly journals Akt phosphorylates and suppresses the transactivation of retinoic acid receptor α

2006 ◽  
Vol 395 (3) ◽  
pp. 653-662 ◽  
Author(s):  
Harish Srinivas ◽  
Dianren Xia ◽  
Nicole L. Moore ◽  
Ivan P. Uray ◽  
Heetae Kim ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Suppressive Effect ◽  
Dominant Negative ◽  
Nsclc Cell Line ◽  
Acid Receptor ◽  
Growth Inhibitory ◽  
Dominant Negative Form ◽  
Retinoic Acid Receptor Α ◽  
Functional Analyses

The transactivation of nuclear receptors is regulated by both ligand binding and phosphorylation. We previously showed that RARα (retinoic acid receptor α) phosphorylation by c-Jun N-terminal kinase contributes to retinoid resistance in a subset of NSCLC cells (non-small cell lung cancer cells), but the aetiology of this resistance in the remainder has not been fully elucidated [Srinivas, Juroske, Kalyankrishna, Cody, Price, Xu, Narayanan, Weigel and Kurie (2005) Mol. Cell. Biol. 25, 1054–1069]. In the present study, we report that Akt, which is constitutively activated in NSCLC cells, phosphorylates RARα and inhibits its transactivation. Biochemical and functional analyses showed that Akt interacts with RARα and phosphorylates the Ser96 residue of its DNA-binding domain. Mutation of Ser96 to alanine abrogated the suppressive effect of Akt. Overexpression of a dominant-negative form of Akt in an NSCLC cell line decreased RAR phosphorylation, increased RAR transactivation and enhanced the growth-inhibitory effects of an RAR ligand. The findings presented here show that Akt inhibits RAR transactivation and contributes to retinoid resistance in a subset of NSCLC cells.

scholarly journals Down-Regulation of the Tumor Suppressor Gene Retinoic Acid Receptor β2 through the Phosphoinositide 3-Kinase/Akt Signaling Pathway

2006 ◽  
Vol 20 (9) ◽  
pp. 2109-2121 ◽  
Author(s):  
Bruno Lefebvre ◽  
Céline Brand ◽  
Sébastien Flajollet ◽  
Philippe Lefebvre
Keyword(s):  
Retinoic Acid ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Retinoic Acid Receptor ◽  
Suppressor Gene ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Down Regulation ◽  
Retinoic Acid Receptor Β2 ◽  
Phosphoinositide 3 Kinase

Abstract The retinoic acid receptor β2 (RARβ2) is a potent, retinoid-inducible tumor suppressor gene, which is a critical molecular relay for retinoid actions in cells. Its down-regulation, or loss of expression, leads to resistance of cancer cells to retinoid treatment. Up to now, no primary mechanism underlying the repression of the RARβ2 gene expression, hence affecting cellular retinoid sensitivity, has been identified. Here, we demonstrate that the phosphoinositide 3-kinase/Akt signaling pathway affects cellular retinoid sensitivity, by regulating corepressor recruitment to the RARβ2 promoter. Through direct phosphorylation of the corepressor silencing mediator for retinoic and thyroid hormone receptors (SMRT), Akt stabilized RAR/SMRT interaction, leading to an increased tethering of SMRT to the RARβ2 promoter, decreased histone acetylation, down-regulation of the RARβ2 expression, and impaired cellular differentiation in response to retinoid. The phosphoinositide 3-kinase/Akt signaling pathway, an important modulator of cellular survival, has thus a direct impact on cellular retinoid sensitivity, and its deregulation may be the triggering event in retinoid resistance of cancer cells.

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