cAMP-induced degradation of cyclin D3 through association with GSK-3β

Naderi, Soheil; Gützkow, Kristine B.; Låhne, Hege U; Lefdal, S; Ryves, W. J.; Harwood, Adrian J.; Blomhoff, Heidi Kiil

doi:10.1242/jcs.01210

Cited by 50 publications

(62 citation statements)

References 59 publications

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“…This is in agreement with previous reports that demonstrated that PI3K pathway plays an essential role in transcriptional activation of the cyclin D2 gene (Chiles, 2004). Recent studies on cyclin D1 and cyclin D3, however, have shown that expression of these D-type cyclins are regulated also at post-transcriptional levels, most significantly at the post-translational level (Diehl et al, 1997(Diehl et al, , 1998Casanovas et al, 2000Casanovas et al, , 2004Naderi et al, 2004). We thus examined the possible involvement of post-translational mechanisms in cytokine regulation of cyclin D2 expression in hematopoietic cells.…”

Section: Resultssupporting

confidence: 90%

“…been reported for cyclin D3; Casanovas et al (2004) demonstrated that p38 but not GSK3b phosphorylates cyclin D3 in vitro at Thr283, whereas Naderi et al (2004) reported that GSK3b phosphorylated Thr283 to trigger proteasomal degradation of cyclin D3. Discordant results have also been reported for cyclin D1 in regard to the physiological significance of GSK3b in Thr286 phosphorylation-mediated degradation.…”

Section: Discussionmentioning

confidence: 98%

“…On the other hand, Casanovas et al (2000) showed that the p38 kinase activated by osmotic stress also phosphorylates Thr286 of cyclin D1 to trigger its ubiquitin/proteasomedependent degradation. Recent reports further showed that Thr283 in cyclin D3, corresponding to Thr286 in cyclin D1, was also targeted by GSK3b or p38 for the ubiquitin/proteasome-dependent degradation (Casanovas et al, 2004;Naderi et al, 2004). Although these observations suggest the common mechanisms for post-translational regulation, D-type cyclins are also regulated in different manners at the post-translational level.…”

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confidence: 99%

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Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

et al. 2007

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Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes cyclin D2 by inhibition of glycogen synthase kinase-3b (GSK3b) through Janus kinase2-dependent activation of phosphatidylinositol 3 0 -kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of cyclin D2, which was mediated by activation of p38. GSK3b and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of cyclin D2 in primary leukemic or myeloma cells. These results indicate that cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3b or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

et al. 2007

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“…We have previously shown that cAMP induces degradation of cyclin D3 in the B-precursor cell line Reh (Naderi et al, 2004). The mechanism was shown to involve phosphorylation of cyclin D3 by the Ser/Thr kinase GSK-3b, which marks the protein for proteasomal degradation.…”

Section: Oa Increases the Degradation Of Cyclin D3mentioning

confidence: 99%

“…Several cyclins have been shown to be targeted for proteasomal degradation by phosphorylation, including cyclin E, cyclin D1 and cyclin D3 (Won and Reed, 1996;Diehl et al, 1997;Naderi et al, 2004). We recently demonstrated that proteasomal degradation of cyclin D3 in Reh cells is dependent on its phosphorylation at Thr-283 by glycogen synthase kinase-3b (GSK-3b) (Naderi et al, 2004). Generally, the phosphorylation state of a protein depends not only on the activity of protein kinases but also on the activity and accessibility of protein phosphatases.…”

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confidence: 99%

Degradation of cyclin D3 independent of Thr-283 phosphorylation

Låhne

Kloster²,

Lefdal³

et al. 2005

Oncogene

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Cyclin D3 has been shown to play a major role in the regulation of cell cycle progression in lymphocytes. It is therefore important to understand the mechanisms involved in the regulation of this protein. We have previously shown that both basal and cAMP-induced degradation of cyclin D3 in Reh cells is dependent on Thr-283 phosphorylation by glycogen synthase kinase-3b (GSK-3b). We now provide evidence of an alternative mechanism being involved in the regulation of cyclin D3 degradation. Treatment of lymphoid cells with okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A), induces rapid phosphorylation and proteasomal degradation of cyclin D3. This degradation is not inhibited by the GSK-3b inhibitors lithium or Kenpaullone, or by substitution of Thr-283 with Ala on cyclin D3, indicating that cyclin D3 can be degraded independently of Thr-283 phosphorylation and GSK-3b activity. Interestingly, in vitro experiments revealed that PP1, but not PP2A, was able to dephosphorylate cyclin D3 efficiently, and PP1 was found to associate with His-tagged cyclin D3. These results support the hypothesis that PP1 constitutively keeps cyclin D3 in a stable, dephosphorylated state, and that treatment of cells with OA leads to phosphorylation and degradation of cyclin D3 through inhibition of PP1.

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A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: Implications for EBV-driven lymphomagenesis in the HIV setting

et al. 2015

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Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein-Barr virus (EBV)-infected primary and fully transformed B-lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative Bcells up-regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV-infected primary B-cells more efficiently bind and internalize p17 proteins as compared with activated B-lymphocytes. The S75X variant bound more efficiently to EBV-infected primary and fully transformed B-lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up-regulation and increased interleukin-6 production. Notably, the S75X variant markedly up-regulated latent membrane protein-1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV 1 B-cell growth promotion. These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting.

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cAMP-induced degradation of cyclin D3 through association with GSK-3β

Cited by 50 publications

References 59 publications

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

Degradation of cyclin D3 independent of Thr-283 phosphorylation

A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: Implications for EBV-driven lymphomagenesis in the HIV setting

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