Cyclins and cancer II: Cyclin D and CDK inhibitors come of age

Hunter, Tony; Pines, Jonathon

doi:10.1016/0092-8674(94)90543-6

Cited by 2,001 publications

(1,386 citation statements)

References 110 publications

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“…In the lower gastrointestinal tract, TGFb serves as a tight regulatory signal controlling cell proliferation through G 1 cell-cycle inhibition that involves pRb activation as well as by sequential inactivation of cyclins and Cdks, such as Cdk4 which associates with one of the D-type cyclins namely D1, D2 or D3 in a context-dependent manner (Quaroni et al, 1979;Hunter and Pines, 1994;Ko et al, 1998). Given its antiproliferative role in various epithelial cells as well as in liver, the TGF-b signaling likely suppresses hepatocellular carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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Transforming growth factor-b (TGF-b) signaling members, TGF-b receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf þ /À mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (Po0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-b signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

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Section: Discussionmentioning

confidence: 99%

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

et al. 2007

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“…Progression through early to mid G1 is dependent upon the activation of cyclin-dependent kinase Cdk4, which requires association with one of the D-type cyclins, D1, D2 or D3 (reviewed in Hunter and Pines, 1994;Sherr, 1994). The three D-type cyclins have variable expression, depending on cell types (Ajchenbaum et al, 1993;Palmero et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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Transforming growth factor-beta 1 (TGF-b1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-b1-mediated cell cycle arrest. TGF-b1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGFb1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no e ect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-b1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-b1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-b1-mediated arrest of intestinal epithelial cell proliferation.

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“…Several studies have reported that the abnormal expression of certain cyclins may be associated with oncogenesis and cancer progression (Motokura et al, 1993). To date, at least eight mammalian cyclin genes have been identified (A, B, C, D 1-3, E, H) on the basis of their different patterns of expression in the phases of the cell cycle (Hunter and Pines, 1994). Among the members of the cyclin gene family, cyclin Dl is the most strongly implicated in human tumorigenesis (Hinds et al, 1994).…”

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confidence: 99%

Expression of cyclin D1 correlates with malignancy in human ovarian tumours

Barbieri

Cagnoli²,

Ragni³

et al. 1997

Br J Cancer

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Summary Cyclin Dl is a cell cycle regulator of G1 progression that has been suggested to play a relevant role in the pathogenesis of several human cancer types. In the current study, the expression of cyclin Dl has been investigated in a series of 33 patients, with benign (10 patients), borderline (five patients) and malignant (18 patients) ovarian disease. Cyclin Dl protein and mRNA content were analysed by Western blotting and reverse transcriptase polymerase chain reaction respectively. The levels of cyclin Dl protein were undetectable in patients with benign disease, detectable in the majority of patients with borderline disease and elevated in those with ovarian carcinomas, being significantly related to the degree of malignancy (carcinoma vs benign, P = 0.0001; benign vs borderline, P = 0.0238). A significant relationship between cyclin Dl expression and tumour proliferative activity was also found (P= 0.000001). Moreover, eight benign lesions, two borderline tumours and 11 carcinomas proved to be suitable for the analysis of cyclin Dl transcript, and emerging data demonstrated significant agreement between protein abundance and mRNA expression. Results from the current study suggest that cyclin Dl expression is associated with the degree of transformation and most probably plays a role in the early development of ovarian malignancy.

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Cyclins and cancer II: Cyclin D and CDK inhibitors come of age

Cited by 2,001 publications

References 110 publications

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Expression of cyclin D1 correlates with malignancy in human ovarian tumours

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