Modification of the retinoic acid signaling pathway by the catalytic subunit of protein kinase-A.

Huggenvik, Jodi I.; Collard, Michael W.; Kim, Yang-Won; Sharma, Raghubir P.

doi:10.1210/mend.7.4.8388997

Cited by 29 publications

(24 citation statements)

References 23 publications

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“…This is in agreement with other data underlining the importance of retinoid phosphorylation for these signalling cross-talks. [14][15][16] Because the in vitro or in vivo retinoid requirements for maturation of these leukemia cells are extremely high, we wanted to investigate a possible link between such nonphysiological requirements for retinoids and an insufficient cyclase-dependent membrane signalling in APL cells.…”

Section: Introductionmentioning

confidence: 99%

A sustained increase in the endogenous level of cAMP reduces the retinoid concentration required for APL cell maturation to near physiological levels

et al. 1998

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cAMP-dependent signal transduction co-operates with retinoids to induce acute promyelocytic leukaemia (APL) cell maturation. The rationale of this work was to determine whether signal cross-talk could be used to decrease the pharmacological doses of retinoids in the treatment of APL. When only the basal level of adenylate-cyclase (AC) activity is present in NB4 cells, up to 1 M concentration of all-trans retinoic acid (RA) is required for full maturation (100%). In these conditions, with only 10 nM RA less than 20% of cells will differentiate. Although the use of membrane receptor agonists to activate AC has been proved to synergize with RA treatment, these agents were never as potent as cell permeant cAMP analogues. Analogues have disadvantages since cleavage by serum and cellular phosphodiesterases generates metabolites which interfere in cellular response. In the present study, we observed cell maturation by engrafting an autonomous Bordetella pertussis AC which steadily delivers natural cAMP into the cell. The enzyme alone had no effect on cell maturation. Importantly, cell maturation was increased in a dose-dependent manner when the bacterial AC (1 ng/ml to 1 g/ml) was used to potentiate the effects of low doses RA (10 nM). More than 50% of cells matured with only 10 nM of RA and 200 ng/ml of B. pertussis AC. The maturation response was significantly increased when lower amounts of enzyme were repetitively added to the culture to compensate for enzymatic decay. These results indicate that a sustained AC activity enhanced cell maturation. We were able to reduce to 3 nM the RA requirement, provided that a minimal amount (20 ng/ml) of B. pertussis AC was added every 12 h in culture. Membrane signalling maintaining high the level of cAMP substantially improved the efficacy of APL cell maturation by retinoids. Therefore, therapeutic benefits are expected by lowering the concentration of RA towards physiological (nanomolar) levels, thus reducing the side-effects of the drug. cAMP-elevating drugs that act on a post-cyclase target (cyclic-nucleotide phosphodiesterases) or cell-targeted drug carriers (cAMP and RA loaded liposomes) should be evaluated as maturation therapies combining the activation of multiple signalling pathways.

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Section: Introductionmentioning

confidence: 99%

A sustained increase in the endogenous level of cAMP reduces the retinoid concentration required for APL cell maturation to near physiological levels

et al. 1998

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“…In addition, although the regulation of nuclear trafficking was not examined, cAMP-dependent protein kinase (PKA) has been shown to decrease the transcriptional activity of RAR␣ and to inhibit the tRA-induced expression of all three retinoic acid receptor mRNAs in PC12, B16 melanoma, and F9 teratocarcinoma cells (11-13). In contrast, other reports indicate that the phosphorylation of RAR␣ on serine 369 by an overexpressed catalytic subunit of PKA increased the transcriptional activity of the receptor in CV-1, HeLa, and COS-1 cells (14,15).Interestingly, potential physiological effector molecules, for example, hormones and growth factors, which may stimulate PKA activity and influence RAR␣ transcriptional activity, have not been examined. Of particular interest in the study of Sertoli cells is the potential signaling interaction of follicle-stimulating hormone (FSH) with RAR␣.…”

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confidence: 96%

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confidence: 96%

Follicle-stimulating Hormone Inhibits All-trans-retinoic Acid-induced Retinoic Acid Receptor α Nuclear Localization and Transcriptional Activation in Mouse Sertoli Cell Lines

Braun

Tribley

Griswold

et al. 2000

Journal of Biological Chemistry

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The regulation of retinoic acid receptor alpha (RAR␣) signal transduction has not been well characterized. In this study, we determined whether all-trans-retinoic acid (tRA) and follicle-stimulating hormone (FSH) modulate RAR␣ receptor subcellular localization, leading to changes in its transcriptional activity and protein expression in mouse Sertoli cell lines. We found that tRA induced the nuclear localization of RAR␣ within 30 min and that longer term exposure increased the receptor transcriptional activity and RAR␣ protein expression. Conversely, FSH suppressed the tRA-induced nuclear localization, transcriptional transactivation, and protein expression of RAR␣. Treatment with two different protein kinase A-selective antagonists reversed the inhibitory actions of FSH on tRA-dependent RAR␣ nuclear localization and transcriptional activity. These results are consistent with the involvement of protein kinase A in mediating the inhibitory effects of FSH. For the first time, we demonstrate a unique signaling convergence between the RAR␣ and the FSH-mediated signaling pathways, which may have significant implications in the testis because both are critical regulators of testis physiology.Vitamin A is required for various fundamental physiological processes including vertebrate development, cellular differentiation, vision, and reproduction (1, 2). The biologically active form of vitamin A is retinoic acid, which includes all-transretinoic acid (tRA) 1 and 9-cis-retinoic acid (3). The biological response of retinoic acid is mediated through two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors, each of which consists of three receptor subtypes, ␣, ␤, and ␥ (4). Retinoid receptors are transcription factors that regulate the transcription of retinoic acid-responsive genes.Retinoid receptors belong to the larger superfamily of steroid/thyroid hormone receptors. Several members of this superfamily including the progesterone, the glucocorticoid, the estradiol, and the peroxisome proliferator-activated receptors are regulated at the level of nuclear trafficking (5-9). It was demonstrated that activation of cellular kinases increased the nuclear translocation and transcriptional activity of these receptors (8, 9). However, little is known about the regulation of RAR␣ subcellular localization and how this may affect its subsequent transcriptional activity. Previously, Tahayato et al. (10) reported that down-regulation of protein kinase C decreased RAR␣ nuclear localization and subsequent retinoic acid response element (RARE)-dependent transcriptional activity. In addition, although the regulation of nuclear trafficking was not examined, cAMP-dependent protein kinase (PKA) has been shown to decrease the transcriptional activity of RAR␣ and to inhibit the tRA-induced expression of all three retinoic acid receptor mRNAs in PC12, B16 melanoma, and F9 teratocarcinoma cells (11-13). In contrast, other reports indicate that the phosphorylation of RAR␣ on serine 369 by an overexpresse...

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“…For example, the chicken PR (23), androgen receptor (24), retinoic acid receptor (25), retinoid X receptor (26), and peroxisome proliferator-activated receptor-␦ (27) can be activated by cAMP signaling, demonstrating that this mode of ligand-independent activation is not exclusive to ER␣. However, human PR (28) cannot be activated ligand-independently via this mechanism, nor can the unliganded glucocorticoid receptor, although cAMP stimulation increases the hormone-dependent responses of these receptors (29,30).…”

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confidence: 99%

Mechanistic Differences in the Activation of Estrogen Receptor-α (ERα)- and ERβ-dependent Gene Expression by cAMP Signaling Pathway(s)

Coleman

Dutertre

El-Gharbawy

et al. 2003

Journal of Biological Chemistry

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Although increases in intracellular cAMP can stimulate estrogen receptor-␣ (ER␣) activity in the absence of exogenous hormone, no studies have addressed whether ER␤ can be similarly regulated. In transient transfections, forskolin plus 3-isobutyl-1-methylxanthine (IBMX), which increases intracellular cAMP, stimulated the transcriptional activities of both ER␣ and ER␤. This effect was blocked by the protein kinase A inhibitor H89 (N-(2-(p-bromocinnamylamino)-ethyl)-5-isoquinolinesulfonamide) and was dependent on an estrogen response element. A 12-O-tetradecanoylphorbol-13-acetate response element (TRE) located 5 to the estrogen response element was necessary for cAMP-dependent activation of gene expression by ER␤ but not ER␣, indicating that the former subtype requires a functional interaction with TRE-interacting factor(s) to stimulate transcription. Both p160 and CREB-binding protein coactivators stimulated cAMP-induced ER␣ and ER␤ transcriptional activity. However, mutation of the two cAMP-inducible SRC-1 phosphorylation sites important for cAMP activation of chicken progesterone receptor or all seven known SRC-1 phosphorylation sites did not specifically impair cAMP activation of ER␣. The E/F domains of ER␣ are sufficient for activation by forskolin/IBMX, and this is accompanied by an increase in receptor phosphorylation. In contrast, cAMP signaling reduces the phosphorylation of the corresponding region of ER␤, and this correlates with the lack of forskolin/IBMX stimulated transcriptional activity. Our data suggest that cAMP activation of ER␣ transcriptional activity is associated with receptor instead of SRC-1 phosphorylation. Moreover, differences in the cofactor requirements, domains of ER␣ and ER␤ sufficient for forskolin/IBMX activation, and the effect of cAMP on receptor phosphorylation indicate that this signaling pathway utilizes distinct mechanisms to stimulate ER␣ and ER␤ transcriptional activity.

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Modification of the retinoic acid signaling pathway by the catalytic subunit of protein kinase-A.

Cited by 29 publications

References 23 publications

A sustained increase in the endogenous level of cAMP reduces the retinoid concentration required for APL cell maturation to near physiological levels

A sustained increase in the endogenous level of cAMP reduces the retinoid concentration required for APL cell maturation to near physiological levels

Follicle-stimulating Hormone Inhibits All-trans-retinoic Acid-induced Retinoic Acid Receptor α Nuclear Localization and Transcriptional Activation in Mouse Sertoli Cell Lines

Mechanistic Differences in the Activation of Estrogen Receptor-α (ERα)- and ERβ-dependent Gene Expression by cAMP Signaling Pathway(s)

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