α‐Amanitin and 5‐fluorouridine inhibition of serumstimulated DNA synthesis in quiescent AKR‐2B mouse embryo cells

Wells, Dilys; Stoddard, L. S.; Getz, Michael J.; Moses, Harold L.

doi:10.1002/jcp.1041000202

Cited by 16 publications

(19 citation statements)

References 50 publications

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“…The previous data indicated that effects on early GO/Gl events might not be the primary mechanism for TGF,1 growth inhibition. Since traverse of the last half of Gi and commitment to DNA synthesis can occur in the absence of new RNA synthesis (34,35) (Table 1), and TGFfi1 can inhibit epithelial cell proliferation when added in late GI (Fig. 2) (10,15,27).…”

Section: Resultsmentioning

confidence: 99%

Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest.

Howe¹,

Draetta²,

Leof³

1991

Mol. Cell. Biol.

180

126

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Transforming growth factor 01 (TGF0I1) is a potent inhibitor of epithelial cell proliferation. We present data which indicate that epithelial cell proliferation is inhibited when TGF,B1 is added throughout the prereplicative Gl phase. Cultures become reversibly blocked in late Gl at the Gl/S-phase boundary. The inhibitory effects of TGFI1 on cell growth occur in the presence of the RNA synthesis inhibitor 5,6-dichloro-1-4-D-ribofuranosylbenzimidazole. Associated with this inhibitory effect is a decrease in the phosphorylation and histone Hl kinase activity of the p34cdc2 protein kinase. These data suggest that TGFIU growth inhibition in epithelial cells involves the regulation of p34cdc2 activity at the Gl/S transition.

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Section: Resultsmentioning

confidence: 99%

Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest.

Howe¹,

Draetta²,

Leof³

1991

Mol. Cell. Biol.

180

126

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“…Inhibitor studies of i-free medium for quiescent, serum-starved murine AKR-2B cells have similarthen shifted into ly shown that hnRNA synthesis is required for entry into the in Fig. 7, 28% of S phase in the first few hours after serum stimulation, but not ilin entered the S in the last few hours (43). lls receiving 10% DRB is a relatively strong inhibitor of mRNA synthesis.…”

Section: Downloaded Frommentioning

confidence: 93%

Post-transcriptional control of the onset of DNA synthesis by an insulin-like growth factor.

Campisi¹,

Pardee²

1984

Mol. Cell. Biol.

114

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The control of eucaryotic cell proliferation is governed largely by a series of regulatory events which occur in the Gl phase of the cell cycle. When stimulated to proliferate, quiescent (GO) 3T3 fibroblasts require transcription, rapid translation, and three growth factors for the growth state transition. We examined exponentially growing 3T3 cells to relate the requirements for Gl transit to those necessary for the transition from the GO to the S phase. Cycling cells in the Gl phase required transcription, rapid translation, and a single growth factor (insulin-like growth factor [IGF] I) to initiate DNA synthesis. IGF I acted post-transcriptionally at a late Gl step. All cells in the Gl phase entered the S phase on schedule if either insulin (hyperphysiological concentration) or IGF I (subnanomolar concentration) was provided as the sole growth factor. In medium lacking all growth factors, only cells within 2 to 3 h of the S phase were able to initiate DNA synthesis. Similarly, cells within 2 to 3 h of the S phase were less dependent on transcription and translation for entry into the S phase. Cells responded very differently to inhibited translation than to growth factor deprivation. Cells in the early and mid-Gl phases did not progress toward the S phase during transcriptional or translational inhibition, and during translational inhibition they actually regressed from the S phase. In the absence of growth factors, however, these cells continued progressing toward the S phase, but still required IGF at a terminal step before initiating DNA synthesis. We conclude that a suboptimal condition causes cells to either progress or regress in the cell cycle rather than freezing them at their initial position. By using synchronized cultures, we also show that in contrast to earlier events, this final, IGF-dependent step did not require new trnscription. This result is in conrast to findings that other growth factors induce new transcription. We examined the requirements for Gl transit by using a chemically transformed 3T3 cell line (BPA31 cells) which has lost some but not all ability to regulate its growth. Early-and mid-Gl-phase BPA31 cells required transcription and translation to initiate DNA synthesis, although they did not regress from the S phase during translational inhibition. However, these cells did not need IGF for entry into the S phase.Eucaryotic cell growth is controlled by regulatory events which occur before the onset of DNA synthesis (2, 14, 23). The presynthesis or Gi phase of the cell cycle is generally viewed as a period during which cells prepare to initiate a round of DNA replication and cell division. In addition, cells in the Gl phase assess the feasibility of these processes in regard to the extracellular environment.Much of our understanding of the nature of growth regulation derives from studies with cultured murine 3T3 fibroblasts. These established, nontumorigenic embryonic cells show a stringent degree of growth control in culture, depending on the environment into which they are placed...

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“…1). Inhibitors of RNA synthesis can block this process, implying that the transcription of certain genes is required for a quiescent cell to reenter the cell cycle (2). The molecular mechanisms that regulate these genes are poorly understood but do not appear to involve the nuclear translocation of the hormone-receptor complex.…”

mentioning

confidence: 99%

Specific stimulation of actin gene transcription by epidermal growth factor and cycloheximide.

Elder¹,

Schmidt²,

Ono³

et al. 1984

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

203

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Stimulation of quiescent AKR-2B mouse embryo cells with epidermal growth factor (EGF) results in a rapid and specific induction of actin mRNA sequences. These mRNAs include those coding for both P-and y-cytoskeletal, but not a-skeletal muscle, actin isotypes. Elongation of nascent RNA chains in isolated nuclei (run-off transcription) demonstrates that the mRNA accumulation is preceded by an increase in actin gene transcription. This increase is transient, however, and is followed by a rapid attenuation of transcriptional activity. An inhibitor of protein synthesis, cycloheximide, was also found to induce 18-and r-actin mRNA accumulation. Furthermore, the simultaneous addition of EGF and cycloheximide produced a synergistic effect on actin sequences in both steady-state nuclear and polysomal RNA. Run-off transcription experiments demonstrate that this synergistic effect results from an increase in the magnitude and duration of actin gene transcription. It is also specific in that a-tubulin gene transcription is not similarly affected. These data suggest the existence of a specific labile repressor of actin gene transcription.The binding of epidermal growth factor (EGF) to specific receptors in the membranes of quiescent cells initiates a variety of biochemical events that can culminate in the initiation of DNA synthesis and cell division (reviewed in ref. 1). Inhibitors of RNA synthesis can block this process, implying that the transcription of certain genes is required for a quiescent cell to reenter the cell cycle (2). The molecular mechanisms that regulate these genes are poorly understood but do not appear to involve the nuclear translocation of the hormone-receptor complex. Indeed, the complex itself is rapidly internalized and degraded several hours prior to the initiation of DNA synthesis (3,4). This observation has led to speculation that a second messenger(s) of hormone action must be responsible for initiating the expression of specific genes required for cell proliferation (1).A major constraint on any proposed mechanism of EGF or second messenger action is the requirement for a high degree of specificity. This consideration arises from several studies that have shown that peptide growth factors regulate a very limited domain of specific genes (5-8). This specificity could be achieved by a specific DNA binding protein acting either as a positive or negative regulator of gene transcription. Although theoretical constraints have been imposed on specific protein-DNA interactions in the context of a mammalian nucleus, these constraints are not absolute and a variety of compensating strategies are available to a eukaryotic cell (9). Therefore, it may be noteworthy that recent studies have shown that inhibitors of protein synthesis can potentiate the induction of specific mRNA sequences by platelet-derived growth factor (7, 10). Although this observation is consistent with a protein repressor of growth-factor-regulated genes, a direct effect on gene transcription rates was not shown.Prompted by a rep...

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α‐Amanitin and 5‐fluorouridine inhibition of serumstimulated DNA synthesis in quiescent AKR‐2B mouse embryo cells

Cited by 16 publications

References 50 publications

Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest.

Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest.

Post-transcriptional control of the onset of DNA synthesis by an insulin-like growth factor.

Specific stimulation of actin gene transcription by epidermal growth factor and cycloheximide.

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