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  • 1
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 162 (1995), S. 256-265 
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Gastrin is transcriptionally responsive to EGF stimulation (Merchant et al., 1991, Mol. Cell. Biol., 11:2686-2696). Consequently, we hypothesized that previously recognized gastrin autocrine loops (Hoosein et al., 1990, Exp. Cell. Res., 186:15-21), might be controlled by autocrine TGFα in human colon carcinoma cells. Therefore, we examined the interaction between these two autocrine growth factors in two colon carcinoma cell lines which utlizie TGFα. The FET cell line requires exogenous TGFα/EGF for optimal growth and has a classical TGFα autocrine loop which is disrupted by TGFα or epidermal growth factor receptor (EGFr) antibodies. The HCT 116 cell line is not dependent on exogenous TGFα/EGF and exhibits a nonclassical TGFα autocrine loop which is not disrupted by neutralizing antibodies to either TGFα itself or the EGFr. Basal gastrin mRNA production is significantly higher in HCT 116 than FET as measured by RNase protection assay. In the FET cells, exogenous EGF stimulates gastrin mRNA production but not in HCT 116. When the TGFα autocrine loop in HCT 116 is disrupted by constitutive expression of antisense TGFα mRNA, the gastrin mRNA level is significantly repressed. In xenografts derived from these antisense clones, TGFα reverted to high expression, and the gastrin mRNA level was again increased. This interaction between the strong TGFα loop in HCT 116 and the gastrin autocrine loop may confer a growth advantage to these colon cells. Such interactions between growth factors may promote enhanced tumorigenicity to transformed cells with these strong, nonclassical autocrine loops. © 1995 Wiley-Liss, Inc.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Cellular Physiology 177 (1998), S. 387-395 
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Previously, we reported that unaggressive, growth factor-dependent FET human colon carcinoma cells downregulated their transforming growth factor alpha (TGFα) expression in a quiescent state (G0/G1) induced by growth factor and nutrient deprivation (Mulder, 1991, Cancer Res., 51:2256-2262). In contrast, highly aggressive, growth factor-independent HCT116 human colon carcinoma cells aberrantly upregulated this autocrine activity in the quiescent state (Mulder, 1991, Cancer Res., 51:2256-2262; Howell et al., 1998, Mol. Cell. Biol., 18:303-313). In this report, the role of autocrine TGFα and the mechanism of its regulation of expression during reentry into the cell cycle from a noncycling growth state were determined in FET cells. Optimal induction of DNA synthesis from a quiescent state in FET cells is dependent upon autocrine TGFα as well as exogenous transferrin and insulin. Reentry into the cell cycle resulting from treatment with exogenous transferrin and insulin resulted in ∼3-fold induction of TGFα expression within 1 hr. TGFα induction was controlled at the transcription level, and the cis-controlling element was localized to the region between bp -370--201 relative to the translation start codon within the TGFα promoter. Thus neutralization of autocrine TGFα protein revealed that the induced TGFα autocrine activity was necessary for DNA synthesis and acted only in the early G1 phase of the cell cycle. Blockade of autocrine TGFα expression early in the cell cycle resulted in the reduction of DNA synthesis, whereas treatment with neutralization antibody at later times had no effect. This suggested that autocrine TGFα functions to initiate cell growth from noncycling states. This was further confirmed by the dependence of FET cells upon autocrine TGFα for colony formation in experiments where the plating density was sufficiently low to generate a lag phase in tissue culture. In contrast, TGFα autocrine activity was not required for exponential phase cells, as evidenced by the failure of TGFα neutralizing antibody to inhibit proliferation in this growth state. Taken together, these results suggest that autocrine TGFα acts primarily in the process of growth initiation by moving cells from a noncycling state back into the cell cycle, rather than supporting cell growth already initiated. J. Cell. Physiol. 177:387-395, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Previously, we described a model culture system for comparing responsiveness of poorly differentiated and well-differentiated human colon carcinoma cells to exogenous growth factors. While polypeptide growth stimulators elicited an up-regulation of c-myc, as well as a mitogenic response in the well-differentiated cells, the poorly differentiated cells were insensitive to exogenous growth stimulators. We now show, by thymidine incorporation experiments and autoradiographic analysis, that transforming growth factors, β1 (TGF-β) abrogated the mitogenic responses to the growth factors epidermal growth factor + insulin + transferrin (lC,50 = 0.8 ng/ml), as well as to nutrients (basal medium; lC50 = 0.2 ng/ml) in the well-differentiated cells. The poorly differentiated cells did not respond to TGF-β. Moreover, TGF-β (10 ng/ml) completely abrogated the growth factor-stimulated up-regulation of c-myc in the TGF-β responsive, well-differentiated colon carcinoma cells. Addition of TGF-β to the TGF-β-responsive, well-differentiated cells, at a time after c-myc had been transiently up-regulated in response to growth stimulatory factors, resulted in a loss of responsiveness to TGF-β. Addition of TGF-β to these cells at increasing time periods after EIT stimulation also resulted in a loss of the TGF-β-induced repression of c-myc. The results suggest an important role for c-myc in the mechanism of action of TGF-β in well-differentiated human colon carcinoma cells.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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