Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation

Laiho, Marikki; DeCaprio, James A.; Ludlow, John W.; Livingston, David M.; Massagué, Joan

doi:10.1016/0092-8674(90)90251-9

Cited by 750 publications

(451 citation statements)

References 54 publications

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“…43 One key regulator of G 1 to S phase transition is pRb, a growth suppressor that becomes functionally inactive when phosphorylated on specific residues. [43][44][45] To confirm pRb under-phosphorylation as a result of TGF-␤ stimulation, we examined the amount of phosphorylation on specific residues known to be involved in cell cycle regulation. The Ser807/ 811 site is phosphorylated by cyclin D1-CDK4 complexes, 32,46 and its phosphorylation status is examined in our study.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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Although valve interstitial cell (VIC) growth is an essential feature of injured and diseased valves, the regulation of VIC growth is poorly understood. Transforming growth factor (TGF)-␤ promotes VIC proliferation in early-stage wound repair; thus, herein, we tested the hypothesis that TGF-␤ regulates VIC proliferation under normal nonwound conditions using low-density porcine VIC monolayers. Cell numbers were counted during a 10-day period, whereas proliferation and apoptosis were quantified by bromodeoxyuridine staining and TUNEL, respectively. The extent of retinoblastoma protein phosphorylation and expression of cyclin D1, CDK 4, and p27 were compared using Western blot analysis. Adhesion was quantified using a trypsin adhesion assay, and morphological change was demonstrated by immunofluorescence localization of ␣-smooth muscle actin and vinculin. TGF-␤-treated VICs were rhomboid; significantly decreased in number, proliferation, and retinoblastoma protein phosphorylation; and concomitantly had decreased expression of cyclin D1/CDK4 and increased expression of p27. TGF-␤-treated VICs adhered better to substratum and had more vinculin plaques and ␣-smooth muscle actin stress fibers than did controls. Thus, the regulation of VIC growth by TGF-␤ is context dependent. TGF-␤ prevents excessive heart valve growth under normal physiological conditions while it promotes cell proliferation in the early stages of repair, when increased VICs are required.

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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“…Expression of SV-LT can overcome a TGF-b1 mediated G 1 arrest in keratinocytes (Pietenpol et al, 1990) and mink lung epithelial cells (Laiho et al, 1990), and this e ect is dependent upon the pRbbinding domain. It is also probably independent of p53 binding, since the HPV E7 protein, which does not bind p53, has a similar e ect (Laiho et al, 1990). However, the absolute requirement for a pRb-binding domain, and the lack of a role for p53 binding, in promoting proliferation is not universal.…”

Section: Discussionmentioning

confidence: 99%

Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain

Varma

Conrad

2000

Oncogene

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“…In mink lung epithelial cells, the e ects of the hormone appear to be due, in some degree, to a decrease in the translational e ciency of Cdk4 mRNA (Ewen et al, 1995). Suppression of Cdk4 synthesis reduces the abundance of cyclin D/Cdk4 complexes, thereby inhibiting Cdk4-dependent pRB phosphorylation (Laiho et al, 1990;Munger et al, 1992). In contrast, TGF-b1 induces the expression of a Cdk4 inhibitor, p15 INK4B , in human keratinocytes (Hannon and Beach, 1994), mink lung epithelial cells (Reynisdottir et al, 1995) and human breast epithelial cells (Sandhu et al, 1997).…”

Section: Discussionmentioning

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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Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation

Cited by 750 publications

References 54 publications

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain

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

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