Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes

White, P. Bruce; Shore, Angharad M.; Clement, Mathew; McLaren, James E.; Soeiro, Inês; Lam, Eric W.‐F.; Brennan, Paul

doi:10.1038/sj.onc.1209255

Cited by 48 publications

(44 citation statements)

References 41 publications

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“…As shown in Figure 4f, exogenous expression of PTEN in Pten-null MEFs reduced the LEF-mediated (Figure 5a), and previous studies have shown that CREB can bind to this CRE (Sicinski et al, 1996). CREB is a substrate of GSK3b (Bullock and Habener, 1998), and its binding site CRE was reported to be important in the activation of cyclin D2 transcription (Sicinski et al, 1996;White et al, 2006). Mutation of the CRE (À352D2-CREm-Luc) dramatically decreased the overall activity of the cyclin D2 promoter, and the transcriptional inhibition by PTEN and GSK3b was also reduced (Figure 5b and c), indicating an essential role of the CRE in TCF-mediated transcriptional activation of cyclin D2.…”

Section: Suppression Of Cyclin D2 Expression By Pten W Huang Et Almentioning

confidence: 57%

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

Huang

et al. 2006

Oncogene

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PTEN, encoding a lipid phosphatase, is a tumor suppressor gene and is mutated in various types of cancers. It is reported to regulate G1 to S phase transition of the cell cycle by influencing the expression, protein stability and subcellular location of cyclin D1. Here, we provide evidence that PTEN modulates the transcription and protein stability of cyclin D2. Targeted deletion of Pten in mouse embryonic fibroblasts (MEFs) endowed cells with greater potential to overcome G1 arrest than wild-type MEFs and led to the elevated expression of cyclin D2, which was suppressed by the introduction of PTEN. We further defined a pathway involving GSK3b and b-catenin/TCF in PTEN-mediated suppression of cyclin D2 transcription. LiCl, an inhibitor of GSK3b, abolished inhibitory effect of PTEN on cyclin D2 expression, and TCF members could directly bind to the promoter of cyclin D2 and regulate its transcription in a CREB-dependent manner. Our results indicate that the downregulation of cyclin D2 expression by PTEN is mediated by the GSK3b/b-catenin/TCF pathway in cooperation with CREB, and suggest a convergence from the PI-3 kinase/PTEN pathway and the Wnt pathway in modulation of cyclin D2 expression.

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Section: Suppression Of Cyclin D2 Expression By Pten W Huang Et Almentioning

confidence: 57%

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

Huang

et al. 2006

Oncogene

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“…It has also been shown that the CCND2 promoter is regulated by transcription factors, such as signal transducer and activator of transcription 5 and SP1. 21 A previous study has suggested the association between CCND2 polymorphisms and another human disease. Three polymorphisms of CCND2 (namely rs3217862, rs3217901 and rs3217933) were significantly associated with ovarian cancer survival.…”

Section: ) the Ht1 [T-c-t-a-t]mentioning

confidence: 98%

CCND2 polymorphisms associated with clearance of HBV Infection

et al. 2010

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Cyclin D2s (CCND2s) are members of the D-type cyclin family. They interact and construct complexes with cyclin-dependent kinase (CDK)4 or 6. The cyclin D2/CDK4 or CDK6 complexes have key roles in controlling the progression of cell cycle from the Gap 1 (G1) phase to the synthesis (S) phase. Overexpression of cyclin D2 is associated with the development of tumors. In this study, we identified 16 sequence variants of CCND2 polymorphisms through direct DNA sequencing in 24 individuals, and 5 common variants were selected for genotyping in larger-scale subjects (n¼1100). Genetic associations of those polymorphisms with hepatitis B virus (HBV) clearance and hepatocellular carcinoma (HCC) outcome among patients with HBV were analyzed. Although no significant association was observed between the polymorphisms and HCC outcome among HBV patients, one common polymorphism in the 5¢-untranslated region (that is, rs1049606) and the most common haplotype (CCND-ht1 [T-C-T-A-T]), however, were significantly associated with HBV clearance (odds ratio¼0.69, P¼0.0002, P corr ¼0.001 and odds ratio¼1.37, P¼0.0009, P corr ¼0.004, respectively). The minor allele frequency of rs1049606 among the spontaneously recovered (SR) group was significantly higher than that of the chronic carrier (CC) group (frequency¼0.403 vs 0.336, P¼0.0002). In contrast, the frequency of CCND-ht1was higher among the CC group than among the SR group (frequency¼0.429 vs 0.374, P¼0.0009). The information identified in this study might provide valuable insights into generating strategies for control of HBV.

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“…The question of whether loss of G s ␣/cAMP signaling directly leads to cyclin D2 deficiency in ␤ cells requires further study, although recent studies in both lymphocytes and ovarian granulosa cells demonstrated that cAMP induces the Ccnd2 gene promoter via binding of PKA-phosphorylated CREB to a CREB binding site (31,32). Cyclin D2 and its associated cyclin-dependent kinase cdk4 have both been shown to be critical regulators of ␤ cell proliferation and ␤ cell mass (3)(4)(5)(6)(7)33).…”

Section: Discussionmentioning

confidence: 99%

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

Xie

Chen

Zhang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The G protein ␣-subunit Gs␣ is required for hormone-stimulated cAMP generation. In pancreatic ␤ cells, Gs␣ mediates the signaling of glucagon-like peptide 1 and other incretin hormones, which are implicated as important regulators of ␤ cell survival and insulin release. Studies have suggested that G s␣/cAMP mediates these actions by stimulating insulin receptor substrate 2 (IRS2) expression. Mice with ␤ cell-specific Gs␣ deficiency (␤GsKO) were generated by mating G s␣-floxed mice to rat insulin II promoter-cre recombinase mice. ␤GsKO mice had poor survival and postnatal growth with low serum insulin-like growth factor 1 levels. ␤GsKO mice also developed severe hyperglycemia and glucose intolerance with severe hypoinsulinemia and reduced islet insulin content and glucose-stimulated insulin release. ␤GsKO mice had markedly reduced average islet size and ␤ cell mass, which was partially explained by reduced ␤ cell size. In addition, ␤GsKO mice had significantly reduced ␤ cell proliferation and increased ␤ cell apoptosis and markedly reduced expression of the cell cycle protein cyclin D2. The effects on ␤ cell mass and proliferation, but not apoptosis, were present from birth. Unexpectedly expression of Irs2 and the downstream gene Pdx1 were unaffected. These results show that G s␣/cAMP pathways are critical regulators of ␤ cell function and proliferation that can work through IRS2-independent mechanisms.

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Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes

Cited by 48 publications

References 41 publications

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

CCND2 polymorphisms associated with clearance of HBV Infection

β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes

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Regulation of cyclin D2 and the cyclin D2 promoter by protein kinase A and CREB in lymphocytes

Cited by 48 publications

References 41 publications

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

GSK3β mediates suppression of cyclin D2 expression by tumor suppressor PTEN

CCND2 polymorphisms associated with clearance of HBV Infection

β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

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β cell-specific deficiency of the stimulatory G protein α-subunit G _s α leads to reduced β cell mass and insulin-deficient diabetes