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 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.

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.

Atiprimod Inhibits the JAK-STAT Pathway and Induces Apoptosis in Human Cells Carrying the JAK2V617F or JAK3 Mutation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3556-3556
Author(s):  
Taghi Manshouri ◽  
Mirna Golemovic ◽  
Hagop M.M. Kantarjian ◽  
Jorge E. Cortes ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Inhibitory Effect ◽  
Erythropoietin Receptor ◽  
Dependent Manner ◽  
Wild Type ◽  
Hematopoietic Progenitors ◽  
Growth Inhibitory Effect ◽  
Megakaryoblastic Leukemia ◽  
Growth Inhibitory ◽  
Mts Assay

Abstract Janus Kinases (JAK), including JAK1, JAK2, TYKa, and JAK3, are a small family of cytoplasmic protein tyrosine kinases, which play an important role in the initiation of cytokine-triggered signaling events by signal transducer and activator of transcription (STAT) proteins, via phosphorylation. The recent reports of an activating somatic mutation in codon 617 of the gene encoding JAK2 (JAK2V617F) in patients with myeloproliferative disorders (MPDs) and 3 mutations in JAK3 (A572V, V722I, P132T) in acute megakaryoblastic leukemia patients, has opened new avenues for the development of targeted therapies for these malignancies. We report here the activity of Atiprimod, a novel compound with anti-inflammatory properties, in retrovirus-transduced JAK2 (JAK2V617F) mutant-expressing murine FDCP-EpoR cells, set-2 cells, CMK cells, and blood cells from patients with polycythemia vera (PV). We compared the growth inhibitory effect of Atiprimod against two mouse FDCP cell lines transfected with erythropoietin receptor (Epo-R), and either wild-type JAK2 (JAK2WT) or mutant JAK2 (JAK2V617F), and human megakaryoblastic leukemia cells with mutated JAK2V617F (set-2 cells) or mutated JAK3 (CMK cells). The growth inhibitory effect was assessed using 3-days MTS assay. Atiprimod was more potent against FDCP cells carrying mutant JAK2 (JAK2V617F) cells (Ic50 0.42 μM) and set-2 cells (Ic50 0.53 μM) than the CMK cells with mutant JAK3 (Ic50 0.79 μM) and FDCP wild-type JAK2 (JAK2WT) cells (Ic50 0.69 μM). Atiprimod, inhibited the phosphorylation of JAK2 and downstream STAT3, STAT5, and AKT proteins in a dose-and time-dependent manner. It exerted its inhibitory activity against cells with mutant JAK2 (JAK2V617F) by affecting the cell cycle progression and induced apoptosis, as evidenced by increase in mitochondrial membrane potential and caspase3 activity. Atiprimod also cleaved PARP protein, increased turnover of the anti-apoptotic X-linked mammalian inhibitor of apoptosis (XIAP) protein, and inhibited the apoptotic protein BCL2 in a time- and dose-dependent manner. In addition, Atiprimod inhibited the proliferation of peripheral blood hematopoietic progenitors from three patients with PV carrying the JAK2 (JAK2V617F) mutation as compared to hematopoietic progenitors from normal individuals, by 2-days MTS assay (p= 0.0013). Our data suggest that Atiprimod is active both in vitro and ex vivo against cells with activated tyrosine kinase of the JAK family.

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