Differential Effects of Cyclic Adenosine 3',5'-Monophosphate on p70 Ribosomal S6 Kinase

Cass, Lisa A.

doi:10.1210/en.139.4.1991

Cited by 39 publications

(50 citation statements)

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“…In our FRTL-5 cell line, forskolin alone does not stimulate DNA synthesis, in agreement with results showing that TSH alone has no effect on DNA synthesis in WRT thyroid cells (6). The cAMP/PKA-dependent pathway has been shown to activate p70-S6 kinase (S6K1) in thyroid cells (7), which is essential for cell cycle progression in many cell types. Although the activation of PKA was necessary for cell cycle progression, it has been suggested that PKA-independent mechanisms might be required in cAMP-mediated growth of thyroid cells (8,9).…”

Section: Introductionsupporting

confidence: 91%

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

Correze¹,

Blondeau²,

Pomérance³

2005

eur j endocrinol

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Objective: Thyrotropin activates the cAMP pathway in thyroid cells, and stimulates cell cycle progression in cooperation with insulin or insulin-like growth factor-I. Because p38 mitogen-activated protein kinases (p38 MAPKs) were stimulated by cAMP in the FRTL-5 rat thyroid cell line, we investigated (i) the effect of the specific inhibition of p38 MAPKs on FRTL-5 cell proliferation and (ii) the mechanism of action of p38 MAPKs on cell cycle control, by studying the expression and/or the activity of several cell cycle regulatory proteins in FRTL-5 cells. Methods: DNA synthesis was monitored by incorporation of [ 3 H]thymidine into DNA and the cell cycle distribution was assessed by fluorescence-activated cell sorter analysis. Expression of cell cycle regulatory proteins was determined by Western blot analysis. Cyclin-dependent kinase 2 (Cdk2) activity associated to cyclin E was immunoprecipitated and was measured by an in vitro kinase assay. Results: SB203580, an inhibitor of a and b isoforms of p38 MAPKs, but not its inactive analog SB202474, inhibited DNA synthesis and the G1-S transition induced by forskolin plus insulin. SB203580 inhibited specifically p38 MAPK activity but not other kinase activities such as Akt and p70-S6 kinase. Treatment of FRTL-5 cells with SB203580 decreased total and cyclin E-associated Cdk2 kinase activity stimulated with forskolin and insulin. However, inhibition of p38 MAPKs by SB203580 was without effect on total cyclin E and Cdk2 levels. The decrease in Cdk2 kinase activity caused by SB203580 treatment was not due to an increased expression of p21Cip1 or p27 Kip1 inhibitory proteins. In addition, SB203580 affected neither Cdc25A phosphatase expression nor Cdk2 Tyr-15 phosphorylation. Inhibition of p38 MAPKs decreased Cdk2-cyclin E activation by regulating the subcellular localization of Cdk2 and its phosphorylation on Thr-160. Conclusions: These results indicate that p38 MAPK activity is involved in the regulation of cell cycle progression in FRTL-5 thyroid cells, at least in part by increasing nuclear Cdk2 activity. 153 123-133 European Journal of Endocrinology

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Section: Introductionsupporting

confidence: 91%

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

Correze¹,

Blondeau²,

Pomérance³

2005

eur j endocrinol

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“…These data unequivocally show the key role of mTOR in inducing thyrocyte proliferation downstream of TSHR. The involvement of S6K1 in TSH-dependent proliferation had been previously suggested by studies in dog and rat thyrocytes (6,9), although the mechanisms of S6K1 activation downstream of TSH had not been defined.…”

Section: Discussionmentioning

confidence: 99%

“…Likely candidates to transduce these mitogenic signals include the cAMP-responsive element binding protein (CREB; ref. 5), p70S6K (6), and the small GTPase Rap1 (7). However, microinjection of Rap1 failed to induce proliferation of dog thyrocytes, showing that Rap1 alone is not sufficient to trigger thyroid cell growth (8).…”

Section: Introductionmentioning

confidence: 99%

Thyroid-Stimulating Hormone–Initiated Proliferative Signals Converge In vivo on the mTOR Kinase without Activating AKT

2007

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Thyroid-stimulating hormone (TSH) has long been recognized as the major proliferative and functional stimulus for thyroid follicular cells. TSH receptor (TSHR) engagement stimulates the production of cyclic AMP and the subsequent activation of downstream effector molecules, including protein kinase A, S6K1, and Rap1, whereas the role of the RAS and phosphatidylinositol-3-kinase signaling cascades downstream of TSHR is still controversial. Despite the abundance of candidates, it is still unclear which of these pathways represent(s) the key mitogenic output of TSH-initiated signaling. We have used an in vivo model of goitrogenesis to dissect the contribution of these pathways to TSH-induced thyrocyte proliferation and thyroid hyperplasia. We show that the in vivo proliferative response to chronic TSHR stimulation relies heavily on the activation of the mTOR/S6K1 axis, and that mTOR inhibition during goitrogenic stimulation abrogates the hyperplastic but not the hypertrophic thyrocyte responses to TSH, thus functionally uncoupling these two processes. Strikingly, goitrogenesis was not associated with an increase in AKT phosphorylation levels, underlining the existence of an AKTindependent pathway leading to mTOR activation upon TSH stimulation. [Cancer Res 2007;67(17):8002-6]

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“…The inhibition of basal and stimulated p70 S6k activity in hepatocytes by glucagon is consistent with studies in other cell types in which cAMP is antiproliferative, 44,45 although stimulation of p70 S6k by agents increasing intracellular cAMP has been shown in cells in which cAMP is mitogenic. 46,47 The inhibition of interleukin-2-stimulated p70 S6k activity in T lymphocytes and smooth muscle cells by cAMP occurs at the level of PI 3-kinase. 44,45 TGF-␤ has no effect on either basal or stimulated levels of cAMP in hepatocytes, 6 and, on the basis of our results, no effect on the activity of PKB or, by inference, PI 3 kinase.…”

Section: Fig 3 Tgf-␤ and Glucagon Do Not Inhibit Egf-induced Jnk1 Omentioning

confidence: 99%

Inhibition of rat hepatocyte proliferation by transforming growth factor ? and glucagon is associated with inhibition of ERK2 and p70 S6 kinase

Dixon¹,

Agius²,

Yeaman

et al. 1999

Hepatology

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Stimulation of hepatocyte proliferation by epidermal growth factor (EGF) and insulin is inhibited by transforming growth factor ␤ (TGF-␤) and by glucagon. It is also suppressed by inhibitors of various protein kinases, including rapamycin, which blocks activation of p70 S6 kinase (p70 S6k ), PD98059, which inhibits the activation of extracellular-regulated kinase (ERK), and SB 203580, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated whether the inhibition of proliferation by TGF-␤ involves these protein kinase cascades. Culture of hepatocytes with TGF-␤ for 16 hours decreased the stimulation by EGF of ERK2 and p70 S6k (by 50% and 35%, respectively), but did not affect the stimulation of either p38 MAPK, c-jun NH 2 -terminal kinase (JNK), or protein kinase B (PKB). Culture of hepatocytes with glucagon for 16 hours also inhibited the stimulation by EGF of activation of ERK2 and p70 S6k (by E50%). The inhibitory effects of glucagon were observed when the hormone was added either 10 minutes or 60 minutes before EGF addition, whereas no effects of TGF-␤ were observed after 10-minute or 60-minute incubation. These results suggest that the inhibition of hepatocyte proliferation by TGF-␤ may be in part mediated by inhibition of ERK2 and p70 S6k , but does not involve PKB, JNK, or p38 MAPK. Unlike glucagon, the effects of TGF-␤ are not elicited in response to short-term treatment. (HEPATOLOGY 1999;29:1418-1424 Hepatocyte proliferation following injury or partial hepatectomy is regulated by the action of both stimulatory (mitogenic) and inhibitory growth factors and hormones (reviewed in Michalopoulos 1 and Fausto 2 ). Studies in primary hepatocyte cultures have identified several complete mitogens capable of inducing DNA synthesis in serum-free medium,

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Differential Effects of Cyclic Adenosine 3',5'-Monophosphate on p70 Ribosomal S6 Kinase

Cited by 39 publications

References 0 publications

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

Thyroid-Stimulating Hormone–Initiated Proliferative Signals Converge In vivo on the mTOR Kinase without Activating AKT

Inhibition of rat hepatocyte proliferation by transforming growth factor ? and glucagon is associated with inhibition of ERK2 and p70 S6 kinase

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