Involvement of plasma membrane glycoproteins in the contact-dependent inhibition of growth of human fibroblasts

Wieser, Raimund; Heck, Rosario; Oesch, Franz

doi:10.1016/0014-4827(85)90472-0

Cited by 42 publications

(41 citation statements)

References 18 publications

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“…FH109 cells were sparsely seeded and cultured for 24 h in DMEM/0.5% FCS to achieve partial synchronization. Control cells were stimulated with 10% FCS in DMEM whereas contact-inhibited cells were generated by the addition of ®xed cells in DMEM/10% FCS prepared from con¯uent cultures (Wieser et al, 1985). These experiments revealed that when ®xed cells were added within the ®rst 8 h after serum-stimulation, proliferation was inhibited by 70 ± 80% as determined by [ 3 H]-thymidine incorporation, which correlates with the reduction of growth rate achieved by seeding ®broblasts to con¯uency (Figure 1).…”

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confidence: 91%

“…In previous studies we have demonstrated that this system mimics physiological conditions concerning cell proliferation and differentiation which occur in con¯uent cultures (Wieser et al, 1985;Wieser and Oesch, 1986), thus enabling the study of early e ects of cell-cell contact-dependent signals. FH109 cells were sparsely seeded and cultured for 24 h in DMEM/0.5% FCS to achieve partial synchronization.…”

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confidence: 99%

“…In order to determine at which point of the G1-phase cells are arrested by contact-dependent inhibition of growth, time course studies were performed. In FH109 cells, human embryonal diploid lung ®broblasts (Wieser et al, 1985), contactdependent inhibition of growth is exclusively mediated by the interaction of two cell membrane proteins on adjacent cells, i.e. by the glycoprotein, contactinhibin (Wieser et al, 1990), which binds to its receptor referred to as contactinhibin receptor (Gradl et al, 1995).…”

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confidence: 99%

“…Correspondence: RJ Wieser Received 13 January 1998; revised 6 July 1998; accepted 7 July 1998 Wieser et al, 1985) were cultured in Dulbecco's modi®ed Eagle's medium (DMEM) with 10% fetal calf serum (FCS; Roth) at 10% CO 2 . Proliferation assay 5610 3 cells were cultured in microtiter plates for 24 h in 100 ml of DMEM/0.5%FCS.…”

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p16INK4 mediates contact-inhibition of growth

Wieser¹,

Faust²,

Dietrich³

et al. 1999

Oncogene

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Growth of non-transformed cells in vitro is regulated by density-dependent mechanisms via cell-cell contacts, leading to arrest in late G1-phase at con¯uency (contact-inhibition of growth). In the present study it is shown that this results from p16 INK4 -mediated dissociation of the complex cdk4-cyclin D1, which is responsible for the inactivation of the gate keeper of G1-S transition, the retinoblastoma protein pRb. As a consequence of the inactivation of cdk4, downstream the activation of cdk2 and hyperphosphorylation and thus inactivation of pRb was impaired. Direct evidence for the central role of p16 INK4 in growth control comes from the observation that a competitive inhibitor of p16 INK4 repressed contact inhibition of growth. These ®ndings provide an explanation for the high incidence of mutation or loss of INK4 in human tumours.Keywords: contact-inhibition; cdk4; p16 INK4 The cell cycle is regulated by an ordered cascade of phosphorylation reactions by a speci®c family of serine-threonine kinases, the cyclin-dependent kinases (cdks) (Lees, 1995;Sherr, 1996), and speci®c check points ensure that the cell's proper cycle is tightly controlled. In order to determine at which point of the G1-phase cells are arrested by contact-dependent inhibition of growth, time course studies were performed. In FH109 cells, human embryonal diploid lung ®broblasts (Wieser et al., 1985), contactdependent inhibition of growth is exclusively mediated by the interaction of two cell membrane proteins on adjacent cells, i.e. by the glycoprotein, contactinhibin (Wieser et al., 1990), which binds to its receptor referred to as contactinhibin receptor (Gradl et al., 1995).Cell-cell contacts were imitated by the addition of glutaraldehyde-®xed cells (in which contactinhibin remains active, as its growth inhibitory activity is mediated exclusively by its N-glycans not a ected by the ®xation process) to sparsely seeded ®broblasts in the presence of serum. In previous studies we have demonstrated that this system mimics physiological conditions concerning cell proliferation and differentiation which occur in con¯uent cultures (Wieser et al., 1985;Wieser and Oesch, 1986), thus enabling the study of early e ects of cell-cell contact-dependent signals. FH109 cells were sparsely seeded and cultured for 24 h in DMEM/0.5% FCS to achieve partial synchronization. Control cells were stimulated with 10% FCS in DMEM whereas contact-inhibited cells were generated by the addition of ®xed cells in DMEM/10% FCS prepared from con¯uent cultures (Wieser et al., 1985). These experiments revealed that when ®xed cells were added within the ®rst 8 h after serum-stimulation, proliferation was inhibited by 70 ± 80% as determined by [ 3 H]-thymidine incorporation, which correlates with the reduction of growth rate achieved by seeding ®broblasts to con¯uency (Figure 1). The addition of ®xed cells 10 h after serum stimulation no longer resulted in any growth inhibition, indicating that contact-dependent inhibition of growth is limited to a window in the cell ...

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confidence: 91%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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p16INK4 mediates contact-inhibition of growth

Wieser¹,

Faust²,

Dietrich³

et al. 1999

Oncogene

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“…Exponentially growing FH109 human embryonal lung ®broblasts (Wieser et al, 1985) were seeded either sparsely or to high density in CG-medium (Vitromex) supplemented with 0.5% fetal calf serum (Gibco). FH109 cells have been shown to highly sensitive to cell-cell contacts with respect to growth-inhibition (Wieser et al, 1985(Wieser et al, , 1990Wieser and Oesch, 1986).…”

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Differences in the mechanisms of growth control in contact-inhibited and serum-deprived human fibroblasts

et al. 1997

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In the present work we studied mechanisms of growth control in contact-inhibited and serum-deprived human diploid ®broblasts. The observation that the e ects on [ 3 H]thymidine incorporation and reduction of retinoblastoma gene product-phosphorylation were additive when contact-inhibition and serum-deprivation were combined led us to the conclusion that the underlying mechanisms might be di erent. Both contact-inhibition and serumdeprivation led to a strong decrease of cdk4-kinaseactivity and cdk2-phosphorylation at Thr 160, while the total amounts of cdk4 and cdk2 remained constant. In contact-inhibited cells, we revealed a strong protein accumulation of the cdk2-inhibitor p27 and a slight, but signi®cant increase of the cdk4-inhibitor p16. In serumdeprived cells, the protein levels in p27 and p16 remained low. In contrast, we detected a rapid decrease of cyclin D1 and cyclin D3 which did not occur in contactinhibited cells. These results indicate that serumdeprivation and contact-inhibition have di erent mechanisms although they a ect the same pathway cyclin D ± cdk4, pRB, cyclin E ± cdk2.

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Homotypic cell contact-dependent inhibition of astrocyte proliferation

Nakatsuji

Miller

1998

Glia

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Involvement of plasma membrane glycoproteins in the contact-dependent inhibition of growth of human fibroblasts

Cited by 42 publications

References 18 publications

p16INK4 mediates contact-inhibition of growth

p16INK4 mediates contact-inhibition of growth

Differences in the mechanisms of growth control in contact-inhibited and serum-deprived human fibroblasts

Homotypic cell contact-dependent inhibition of astrocyte proliferation

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