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C D Stiles

Publications and source records attributed to C D Stiles.

At least 73 records · Page 4Linked to original sources
PubMed1989

Evidence for a novel signal transduction pathway activated by platelet-derived growth factor and by double-stranded RNA.

Platelet-derived growth factor (PDGF) and the synthetic double-stranded RNA poly(I).poly(C) [poly(I.C)] stimulate transcription of the JE gene in BALB/c-3T3 fibroblasts. The response of JE to poly(I.C) does not appear to be channeled through any known component of the PDGF receptor signal transduction apparatus. In addition, JE sequences upstream of the transcription start site are devoid of previously identified poly(I.C)-responsive elements, such as those found in the beta-interferon gene. These data suggest that a novel signal transduction pathway regulates the JE response to PDGF and double-stranded RNA. The c-myc and c-fos proto-oncogenes also respond to this pathway but with poor efficiency. However, this pathway operates very efficiently on other PDGF-inducible genes that encode the secretory proteins KC and M-CSF.

1-Phosphatidylinositol 4-Kinase↗
PubMed1989

Labile repressors are involved in the transcriptional control of PDGF-responsive genes.

Platelet-derived growth factor (PDGF) stimulates the transcription of a number of genes in BALB/c-3T3 fibroblasts. Some of these genes (notably the c-myc and c-fo proto-oncogenes) are induced also by phorbol-based tumor promoters which activate protein kinase C. It appears that the response of these genes to PDGF is actually channeled through the activation of protein kinase C. However, other PDGF-inducible genes such as JE, KC, and JB do not respond to tumor promoter. Data suggest that a labile repressor protein blocks the transcriptional response of these genes to tumor promoter. This labile repressor is specific for elements in the JE, KC, and JB genes for it has no effect on the activation of the SV40 early promoter, which is a known target for phorbol ester-inducible transativation.

Animals↗
PubMed1988

Platelet-derived growth factor A chain is maternally encoded in Xenopus embryos.

Transcription of zygotic genes does not occur in early Xenopus embryos until the mid-blastula transition, 6 to 7 hours after fertilization. Before this time, development is directed by maternal proteins and messenger RNAs stored within the egg. Two different forms of the A chain of platelet-derived growth factor (PDGF) are shown here to be encoded by maternal messenger RNAs. The two forms closely resemble human PDGF; however, the long form contains a hydrophobic region near the carboxyl terminus. The presence of PDGF messenger RNA in the embryo supports the idea that endogenous growth factors act at the earliest stages of embryogenesis.

Amino Acid Sequence↗
PubMed1988

Regulation of c-myc and c-fos proto-oncogene expression by animal cell growth factors.

Animal cell growth factors stimulate expression of the proto-oncogenes c-myc and c-fos. The products of these genes seem to act as intracellular mediators of the mitogenic response to growth factors. Phosphatidyl inositol breakdown products function as cytoplasmic second messengers to induce transcription of c-myc and c-fos although they may not play an exclusive role in this regard. Post-transcriptional events may contribute to the modulation of c-myc gene expression. Following induction, the c-myc and c-fos mRNAs are selectively degraded within the cell.

Animals↗
PubMed1988

Cloning and expression of JE, a gene inducible by platelet-derived growth factor and whose product has cytokine-like properties.

The platelet-derived growth factor-inducible gene JE has been widely used as a molecular marker for the cellular response to growth factors, antimitogenic agents, and other biological response modifiers; however, the structure of the JE gene and the nature of its encoded protein have not been previously described. We present here structural and regulatory features of the JE gene and its product that link it to a family of cytokines, including macrophage colony-stimulating factor, interferon alpha, interleukin 6 (also known as interferon beta 2, B-cell-stimulatory factor 2, 26-kDa protein, and hybridoma/plasmacytoma growth factor), and interleukin 2. Just as T lymphocytes secrete interleukins as a component of their response to mitogens, it appears that fibroblasts secrete cytokines as a component of their response to platelet-derived growth factor.

Amino Acid Sequence↗
PubMed1988

Platelet-derived growth factor generates at least two distinct intracellular signals that modulate gene expression.

Regulation of the genes by PDGF has some common features. All are primary response genes, and they can still be expressed in the presence of cycloheximide (Cochran et al. 1983; Kelly et al. 1983; Kruijer et al. 1984; Lau and Nathans 1985). In fact, many of the genes are superinduced when cells are treated with growth factors plus cycloheximide (Greenberg et al. 1986). The genes that have been characterized all contain a sequence motif in their 3'-noncoding sequences that appears to make the message labile (Meijlink et al. 1985; Treisman 1985; Shaw and Kamen 1986). All competence genes so far examined are controlled at least in part at the level of transcription (Cochran et al. 1983; Edwards et al. 1985; Almendral et al. 1988). Differences in regulation of the genes include variations in the time course of induction, ranging from 10 minutes to over 4 hours, and differences in the persistence of the mRNAs after their synthesis (Cochran et al. 1983; Muller et al. 1984; Lau and Nathans 1987). The data presented in this paper strongly suggest that multiple, distinct intracellular signals that lead to the expression of multiple genes are generated when cells are treated with growth factors such as PDGF. The variation in the time course of induction of PDGF-inducible genes suggests several models of signal transduction. Four such models are presented in Figure 5. One possibility (Fig. 5A) is that one signal is generated by the interaction of PDGF with its receptor and that this signal activates the very early genes, such as c-fos.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Growth factor superfamilies and mammalian embryogenesis.

With the availability of amino acid and nucleotide sequence information has come the realization that growth factors can be clustered in to superfamilies. Several of these superfamilies contain molecules that were not initially identified because of growth-promoting activities; rather they were discovered through their ability to regulate other processes. Certain members of these superfamilies are present during early mammalian embryogenesis. However, until recently, it has been difficult to manipulate the developing mammalian embryo to observe directly the effects of inappropriate, excessive, or reduced expression of these molecules. Despite this limitation, at least some of these molecules have been implicated in the control of differentiation and morphogenesis, two actions unpredicted from the cell biology of most of the growth factors. Moreover, these actions are reflected in nonmammalian species where homologues of the mammalian growth factors control crucial steps in the choice of developmental fate. This review describes five growth factor superfamilies and the role these molecules may have in controlling proliferation, differentiation, and morphogenesis during mammalian development.

Animals↗
PubMed1987

A cell-cycle constraint on the regulation of gene expression by platelet-derived growth factor.

In density-arrested monolayer cultures of Balb/c 3T3 cells, platelet-derived growth factor (PDGF) stimulates expression of the c-myc and c-fos proto-oncogenes, as well as the functionally uncharacterized genes, JE, KC, and JB. These genes are not coordinately regulated. Under ordinary conditions, c-fos, JE, KC, and JB respond to PDGF only when the cells are in a state of G0 growth arrest at the time of PDGF addition. The c-myc gene is regulated in opposition to the other genes, responding best to PDGF in cycling cultures.

Animals↗
PubMed1987

Platelet-derived growth factor-inducible genes respond differentially to at least two distinct intracellular second messengers.

Platelet-derived growth factor (PDGF) stimulates expression of the c-myc, c-fos, JE, and KC genes in BALB/c/3T3 cells. Here we show that these genes respond differentially to at least two distinct intracellular second messengers generated by PDGF. A broad body of data support the view that response of the c-myc and c-fos genes to PDGF is channeled, at least in part, through activation of protein kinase C. Both PDGF and protein kinase C agonists stimulate transcription of c-myc and c-fos. Down regulation of protein kinase C inhibits the transcriptional induction of c-fos and c-myc by PDGF. In contrast, protein kinase C agonists do not stimulate transcription of JE and KC. Down regulation of protein kinase C does not inhibit the ability of PDGF to stimulate transcription of JE and KC. The differential response of these four genes to PDGF and 12-O-tetradecanoylphorbol-13-acetate correlates with differential phosphorylation of specific intracellular proteins. PDGF treatment stimulates phosphorylation of intracellular proteins at 31, 32, and 80 kilodaltons. Down regulation of protein kinase C prevents phosphorylation of the 80-kDa protein in response to PDGF, but phosphorylation of the smaller proteins is not affected. Finally, PDGF which induces all four genes (and stimulates phosphorylation of three proteins) is a much more potent mitogen than protein kinase C agonists which regulate only some of these events.

Animals↗
PubMed1987

Molecular cloning of gene sequences that are regulated by insulin-like growth factor I.

Insulin-like growth factor I (IGF I) regulates the expression of a select few genes in quiescent BALB/c-3T3 cells. This was demonstrated by gel electrophoresis of radiolabeled proteins and by molecular cloning of twelve distinct IGF I-regulated cDNAs. Together, the electrophoretic and cloning data show that IGF I stimulates the expression of about 0.15% of the genes expressed by 3T3 cells, perhaps 30 genes in total. The genes encode both cytoplasmic and nuclear proteins. At the regulatory level the IGF I-controlled genes segregate into two categories. Category I genes (the minority) respond preferentially to IGF I. Their induction is prevented by actinomycin D, and they are superinduced by the combination of IGF I and anisomycin. Category II genes (the majority) respond to platelet-derived growth factor as well as to IGF I. The response of category II genes to IGF I is insensitive to actinomycin D. The data indicate that category II genes are constitutively transcribed and that IGF I regulates stability of the transcripts. The expression of category II genes correlates well with the ability of 3T3 cells to survive in serum-free culture medium.

Animals↗
PubMed1987

Regulation of c-myc and c-fos mRNA levels by polyomavirus: distinct roles for the capsid protein VP1 and the viral early proteins.

The levels of c-myc, c-fos, and JE mRNAs accumulate in a biphasic pattern following infection of quiescent BALB/c 3T3 mouse cells with polyomavirus. Maximal levels of c-myc and c-fos mRNAs were seen within 1 hr and were nearly undetectable at 6 hr after infection. At 12 hr after infection mRNA levels were again maximal and remained elevated thereafter. Empty virions (capsids) and recombinant VP1 protein, purified from Escherichia coli, induced the early but not the late phase of mRNA accumulation. Virions, capsids, and recombinant VP1 protein stimulated [3H]thymidine nuclear labeling and c-myc mRNA accumulation in a dose-responsive manner paralleling their affinity for the cell receptor for polyoma. The second phase of mRNA accumulation is regulated by the viral early gene products, as shown by polyomavirus early gene mutants and by a transfected cell line (336a) expressing middle tumor antigen upon glucocorticoid addition. These results suggest that polyomavirus interacts with the cell membrane at the onset of infection to increase the levels of mRNA for cellular genes associated with cell competence for DNA replication, and subsequently these levels are maintained by the action of the early viral proteins.

Animals↗
PubMed1986

Cell cycle dependent genes inducible by different mitogens in cells from different species.

A number of genes and cDNA sequences (including at least four oncogenes) are known to be expressed in a cell cycle-dependent manner, i.e. the levels of specific mRNAs vary with the phases of the cell cycle. In order to explore the significance of some of these sequences in the mitogenic response, we have investigated the expression of 8 cell cycle-dependent sequences (plus two control sequences, not expressed in a cell cycle-dependent manner) under a variety of conditions. These conditions included cells of different types, from different species, stimulated to proliferate by different mitogens. The genes (or sequences) studied included five cDNA clones whose sequences are preferentially expressed in early G1, i.e. two cDNA clones inducible by platelet-derived growth factor (JE-3 and KC-1), and three cDNA clones inducible by serum (2A9, 2F1, 4F1); and three oncogenes (c-myc, c-rasHa and p53) whose expression is known to be cycle-dependent. All of the tested genes, except 2A9, c-rasHa and the control genes, are expressed in a cell cycle-dependent manner in human peripheral blood mononuclear cells stimulated by phytohemagglutinin and in serum-stimulated mouse and Syrian hamster fibroblasts. The inducibility of these genes by different mitogens in cells of different types and from different species strongly suggests that these genes play a role in cell cycle progression. This conclusion is further supported by the known structural and functional similarities between cell-cycle dependent genes, oncogenes and genes coding for cell-cycle related molecules.

Animals↗
PubMed1985

The PDGF-inducible 'competence genes': intracellular mediators of the mitogenic response.

We have described a new gene family within mammalian cells. Transcription of this gene family is coordinately induced when BALB/c-3T3 cells are exposed to platelet-derived growth factor. At least two cellular proto-oncogenes (c-myc and c-fos) are members of this gene family, which we term 'competence'. At least one competence gene, c-myc, functions as an intracellular mediator of the mitogenic response to PDGF. Expression of the competence gene family may be a central component of the mitogenic response in fibroblasts, lymphocytes and regenerating liver.

Animals↗
PubMed1985

Platelet-derived growth factor and double-stranded ribonucleic acids stimulate expression of the same genes in 3T3 cells.

Platelet-derived growth factor (PDGF) stimulates expression of a "competence" gene family in Balb/c-3T3 cells. The competence family contains the c-myc and c-fos genes together with several functionally uncharacterized genes (JE, KC, and r-fos) that have been isolated as cDNA clones. We show that double-stranded ribonucleic acid is a potent inducer of the competence gene family. Infection with vesicular stomatitis virus also induces expression of this gene family. Conversely, PDGF stimulates expression of genes hitherto characterized as responsive to double-stranded ribonucleic acids, including the beta-fibroblast interferon and (2'-5')-oligoadenylate synthetase genes. These PDGF-inducible genes could conceivably function in a feedback loop to control 3T3 cell growth. Some of the genes, such as c-fos and c-myc, are induced quickly by PDGF and may initiate a round of cell division. Others, such as beta-fibroblast interferon and (2'-5')-oligoadenylate synthetase, are induced more slowly and may function as feedback inhibitors of the growth response to PDGF.

2',5'-Oligoadenylate Synthetase↗
PubMed1985

The biological role of oncogenes--insights from platelet-derived growth factor: Rhoads Memorial Award lecture.

No one in tumor biology can now be unaware of the overlap between growth factors and oncogenes. Many if not all oncogenes are now perceived as functional components of a mitogenic cascade which is normally controlled by growth factors. Some oncogenes function at the onset of this cascade by directing the synthesis of an automitogenic growth factor. Others function in the interior of the cascade by directing synthesis of a growth factor receptor or a structurally altered receptor derivative. Still other oncogenes appear to be mutated or rearranged homologues of genes the expression of which is normally induced by growth factors. Those of us working with platelet-derived growth factor (PDGF) take particular satisfaction in this new conceptual framework. It is within the molecular biology of PDGF that the overlap between growth factors and oncogenes is illustrated to its fullest and most tangible extent. An oncogene termed c-sis directs synthesis of a functional PDGF subunit. The PDGF receptor protein is in all probability encoded by a member of the src family of oncogenes. Formation of the PDGF:receptor complex stimulates expression of the c-myc and c-fos protooncogenes. My associates and I have devoted the past 10 years to the molecular biology of PDGF. Our studies on the control of the 3T3 cell cycle by PDGF contributed a pair of new jargon terms to the oncology literature--"competence" and "progression." We also had some input into the bottom end of the "oncogene hierarchy" displayed in Chart 1. The effort that we invested paid a pleasant dividend for me when, in the spring of 1984, the American Association for Cancer Research honored me with the Rhoads Memorial Award. What follows is an overview of the PDGF literature which is more anecdotal than comprehensive. My object is to show how the PDGF field moved from the level of whole animal biology, through biochemistry, down to molecular genetics in just 10 years time.

Animals↗