Epidermal growth factor (EGF) is required only during the traverse of early G1 in PDGF stimulated density-arrested BALB/c-3T3 cells

Leof, Edward B.; Wyk, Judson J. Van; O’Keefe, Edward J.; Pledger, W. J.

doi:10.1016/0014-4827(83)90285-9

Cited by 94 publications

(44 citation statements)

References 12 publications

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“…Although EGF stimulates progress through the Go-to G1-phase interval (23) and induces c-fos and c-myc expression during this period (32,33), it did not induce c-ras-Ha mRNA at this time; rather, EGF acted later in the G1 phase to sustain and further elevate this mRNA. It is well established that EGF is a slow-acting mitogen; it must be present for several hours before it can stimulate DNA synthesis (11).…”

Section: Characterization Of C-ras-ha Inductionmentioning

confidence: 85%

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c-ras-Ha gene expression is regulated by insulin or insulinlike growth factor and by epidermal growth factor in murine fibroblasts.

Lu¹,

Levine²,

Campisi³

1989

Mol. Cell. Biol.

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Although much is known about the structure of ras-encoded proteins, little is known about how expression is regulated. In serum-stimulated murine fibroblasts, c-ras-Ha mRNA levels fluctuated with the growth state but not with the position in the cell cycle. Two types of growth factors regulated c-ras-Ha expression: insulin (IN) Qr insulinlike growth factor I, each apparently acting through its cognate receptor, and epidermal growth factor (EGF). In quiescent cells, IN or insulinlike growth factor I induced c-ras-Ha mRNA three-to fivefold within 4 h, but thereafter the mRNA declined. By contrast, EGF had little effect in 4 h but induced the mRNA after 4 to 6 h. When quiescent cells were given serum c-ras protooncogenes are normal cellular genes that are expressed in most cell types, both proliferating and terminally differentiated, but have the potential to play a causative role in the neoplastic transformation of certain cells (2). ras genes encode a family of membrane-associated proteins (p21 proteins) that bind and hydrolyze GTP. Structural and biochemical analyses suggest that p21 proteins function analogously to GTP-binding proteins (G proteins) that couple occupied receptors to intracellular signalling systems (20). The receptors coupled to ras are unknown, but they are presumed to deliver positive mitogenic signals.The primary mechanism by which ras protooncogenes are converted to transforming genes is a point mutation at one of three major sites in the coding sequence (2). In most cases, these point mutations diminish or abolish GTPase activity, which by analogy with other G proteins, should enhance receptor-generated signals. Indeed, when ras proteins bearing one of these point mutations are introduced into mammalian fibroblasts, the cells initiate DNA synthesis and undergo phenotypic changes characteristic of growth factorstimulated or transformed cells (15,22,36).Depending upon the cell type, the oncogenic potential of ras genes can also be manifest when the protooncogene is overexpressed (7,31,34). For example, a point mutation in an intron of the c-ras-Ha gene is apparently responsible for elevated expression of this gene in the human bladder carcinoma cell line T24/EJ; although the c-ras-Ha gene in T24/EJ cells also carries a mutation that diminishes GTPase activity, the mutation that confers overexpression is at least partially responsible for the transforming activity of the c-ras-Ha gene in these cells (10 sis when microinjected into fibroblasts that have been stimulated to proliferate by serum growth factors (26). Together, these findings suggest that the level of c-ras-Ha expression must be carefully controlled for regulated proliferation of normal cells.Despite the importance of c-ras expression for normal cell proliferation, the physiological signals that regulate these genes are largely unknown. This is in striking contrast to c-fos and c-mnc protooncogenes, which encode nuclear proteins (3) and for which the mechanisms of regulation by growth factors and intracellular mediators of growth ...

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Section: Characterization Of C-ras-ha Inductionmentioning

confidence: 85%

“…The requirements for EGF and IGF-I bisect the transition into two intervals of 6 to 7 h each (6,23,24). The first interval (Go to G1) requires primarily EGF, but there is also a requirement for IGF-I during this period; during the second interval (G1 to S), cells require only IGF-I.…”

Section: Characterization Of C-ras-ha Inductionmentioning

confidence: 99%

c-ras-Ha gene expression is regulated by insulin or insulinlike growth factor and by epidermal growth factor in murine fibroblasts.

Lu¹,

Levine²,

Campisi³

1989

Mol. Cell. Biol.

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“…Thus, the mitogenic response results from the combined effects of PDGF-induced competence and "progression factors" such as epidermal growth factor and insulin-like growth factor I (27,28 (Fig. 4A).…”

Section: Methodsmentioning

confidence: 99%

The platelet-derived growth factor alpha-receptor is encoded by a growth-arrest-specific (gas) gene.

Lih

Cohen

Wang

et al. 1996

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

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Using the Escherichia coli lacZ gene to identify chromosomal loci that are transcriptionally active during growth arrest of NIH 3T3 fibroblasts, we found that an mRNA expressed preferentially in serum-deprived cells specifies the previously characterized alpha-receptor (alphaR) for platelet-derived growth factor (PDGF), which mediates mitogenic responsiveness to all PDGF isoforms. Both PDGFalphaR mRNA, which was shown to include a 111-nt segment encoded by a DNA region thought to contain only intron sequences, and PDGFalphaR protein accumulated in serum-starved cells and decreased as cells resumed cycling. Elevated PDGFalphaR gene expression during serum starvation was not observed in cells that had been transformed with oncogenes erbB2, src, or raf, which prevent starvation-induced growth arrest. Our results support the view that products of certain genes expressed during growth arrest function to promote, rather than restrict, cell cycling. We suggest that accumulation of the PDGFalphaR gene product may facilitate the exiting of cells from growth arrest upon mitogenic stimulation by PDGF, leading to the state of "competence" required for cell cycling.

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“…A31 cells are a spontaneously immortal, nontumorigenic mouse embryo cell line whose growth in culture depends on exogenous growth factors. Quiescent A31 cells enter the S phase of the cell cycle only when growth factors are provided in a specific order: first PDGF, then epidermal growth factor (EGF) and a submitogenic dose of insulin-like growth factor I (IGF-I), and finally IGF-I (15)(16)(17). To determine which of these growth factors require ras proteins for their activity, we injected an anti-ras antibody into synchronized A31 cells.…”

mentioning

confidence: 99%

Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts.

Campisi

1992

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

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Epidermal growth factor (EGF) is required only during the traverse of early G1 in PDGF stimulated density-arrested BALB/c-3T3 cells

Cited by 94 publications

References 12 publications

c-ras-Ha gene expression is regulated by insulin or insulinlike growth factor and by epidermal growth factor in murine fibroblasts.

c-ras-Ha gene expression is regulated by insulin or insulinlike growth factor and by epidermal growth factor in murine fibroblasts.

The platelet-derived growth factor alpha-receptor is encoded by a growth-arrest-specific (gas) gene.

Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts.

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