Growth stimulation by coexpression of transforming growth factor-alpha and epidermal growth factor-receptor in normal and adenomatous human colon epithelium.

Markowitz, Sanford D.; Molkentin, Kay F.; Gerbic, Catherine; Jackson, JE; Stellato, Thomas A.; Willson, James K.V.

doi:10.1172/jci114709

Cited by 129 publications

(58 citation statements)

References 31 publications

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“…A number of epithelial tumor cells with increased expression of EGFR also produce its ligands, and therefore, leading to enhanced autocrine growth stimulation Van de Vijver et al, 1991;Atlas et al, 1992). EGFR and TGF-alpha are expressed in human colorectal carcinomas (Malden et al, 1989) and in a number of colorectal carcinoma-derived human cell lines (Co ey et al, 1986;Markowitz et al, 1990;Untawalwe et al, 1993). In recent years, approaches involving interference with and/or blocking of EGFRmediated autocrine growth stimulation by anti-EGFR mAbs have been the subject of active investigation in an e ort to control cell proliferation (Mendelsohn 1990).…”

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confidence: 99%

Nuclear targeting of Bax during apoptosis in human colorectal cancer cells

et al. 1998

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Homeostasis in colonic epithelial cells is regulated by the balance between proliferative activity and cell loss by apoptosis. Because epithelial cells at the apex of colonic crypts undergo apoptosis and proliferative activity is usually restricted to the base of the crypts, it has been proposed that the limited availability of growth factorsignals at the upper portions of the crypts may trigger apoptosis. In the present studies, we investigate the mechanism of apoptosis mediated by growth factor deprivation in colorectal carcinoma cells by delineating the possible involvement of Bax and its subcellular localization. We report that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase activity and downregulation of EGFR by anti-EGFR mAb 225 induces apoptosis in human colorectal carcinoma DiFi and FET cells. Induction of apoptosis was preceded by enhanced expression of newly synthesized Bax protein, and required protein synthesis. In the mAb 225-treated cells, Bax was redistributed from the cytosol to the nucleus and subsequently, to the nuclear membranes. The observed induction of Bax expression by mAb 225 was not associated with p53 induction. However, mAb 225 treatment also triggered relocalization of p53 from the cytosol to a nuclear membrane-bound form. Induction of Bax and its redistribution to the nucleus of DiFi cells during apoptosis was also demonstrated in response to butyrate, a physiological relevant molecule in colonic epithelial cells as it is the principal short-chain fatty acid produced by bacterial fermentation of dietary ®ber in colonic epithelium. Using immuno¯uorescence and confocal microscopy, we observed that Bax is predominantly localized in the cytosol, but during apoptosis it is localized both inside and along the nuclear membrane. Taken together, these ®ndings suggest that apoptosis induced by growth factor-deprivation or butyrate may involve the subcellular redistribution of Bax in human colorectal carcinoma cells.

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confidence: 99%

Nuclear targeting of Bax during apoptosis in human colorectal cancer cells

et al. 1998

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“…The importance of EGFr activation in the regulation of TGFa, either by EGF or TGFa itself, has been established by the use of EGFr antibodies (Markowitz et al, 1990;Ennis et al, 1989;Imanishi et al, 1989). Although the TGFa promoter has been isolated, little is known about the mechanism of response to EGFr activation.…”

Section: Discussionmentioning

confidence: 99%

“…The use of neutralizing antibodies to both TGFa and the EGFr, and TGFa antisense approaches have all demonstrated that TGFa is an autocrine growthstimulatory factor in colon carcinoma (Markowitz et al, 1990;Burgess, 1991, 1992;Ziober et al, 1993) as well as other tumors Ennis et al, 1989;Imanishi et al, 1989;Malden et al, 1989;Lee et al, 1991). TGFa has also been shown to be an autocrine growth factor in normal cells (Markowitz et al, 1990;Malden et al, 1989;Co ey et al, 1987;Madtes et al, 1988;Bates et al, 1990;Kudlow and Bjorge, 1990;Lewis et al, 1990) and during development (Wilcox and Derynck, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…TGFa has also been shown to be an autocrine growth factor in normal cells (Markowitz et al, 1990;Malden et al, 1989;Co ey et al, 1987;Madtes et al, 1988;Bates et al, 1990;Kudlow and Bjorge, 1990;Lewis et al, 1990) and during development (Wilcox and Derynck, 1988). However, solid tumors generally produce higher levels of this growth factor than their normal counterparts .…”

Section: Introductionmentioning

confidence: 99%

“…Increased TGFa protein secretion into culture media is also observed with similar kinetics. Activation of the EGFr has been implicated in this autoinduction as neutralizing antibodies to EGFr inhibit both TGFa accumulation into the media and the growth of many types of tumor cells in vitro (Markowitz et al, 1990;Ennis et al, 1989;Imanishi et al, 1989). Furthermore, overexpression of TGFa in the weakly tumorigenic colon carcinoma cell line GEO by stable transfection of a TGFa expression vector resulted in the isolation of clones with increased tumorigenicity both in vitro and in vivo (Ziober et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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The EGF/TGFα response element within the TGFα promoter consists of a multi-complex regulatory element

et al. 1999

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Role of heparin‐binding EGF‐related peptides in proliferation and apoptosis of activated ras ‐stimulated intestinal epithelial cells

Zushi

Shinomura

Kiyohara

et al. 1997

Intl Journal of Cancer

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The ras mutation is a common and critical step in carcinogenesis. Autocrine growth factors are also known to play an important role in cancer cell growth and transformation. However, the contribution of autocrine growth factors in regulation of proliferation and apoptosis of activated ras‐stimulated intestinal epithelium is not fully understood. Therefore, we constructed activated ras‐transfected intestinal epithelial cell clones (IEC‐ras) to examine the role of epidermal growth factor (EGF)‐related peptides in the behavior of IEC‐ras. Overexpression of EGF family growth factors (transforming growth factor α, heparin‐binding EGF‐like growth factor, amphiregulin and betacellulin) and stronger phosphorylation of the EGF receptor was observed in IEC‐ras compared with control cells. IEC‐ras proliferated more rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG1478, abolished the increased proliferation of IEC‐ras. Heparitinase and chlorate also prevented increased proliferation of IEC‐ras. Additionally, IEC‐ras expressed more bcl‐2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG1478 suppressed bcl‐2 expression and inhibited resistance to apoptosis of IEC‐ras. Heparitinase and chlorate had effects similar to those of AG1478. Our data indicate that heparin‐binding EGF family growth factors play an important role in both increased proliferation and resistance to apoptosis of ras‐stimulated intestinal epithelial cells. Int. J. Cancer 73:917–923, 1997. © 1997 Wiley‐Liss, Inc.

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Growth stimulation by coexpression of transforming growth factor-alpha and epidermal growth factor-receptor in normal and adenomatous human colon epithelium.

Abstract: Autocrine stimulation of the epidermal growth factor receptor (EGF-R), by coexpression of transforming growth factor-a

Cited by 129 publications

References 31 publications

Nuclear targeting of Bax during apoptosis in human colorectal cancer cells

Nuclear targeting of Bax during apoptosis in human colorectal cancer cells

The EGF/TGFα response element within the TGFα promoter consists of a multi-complex regulatory element

Role of heparin‐binding EGF‐related peptides in proliferation and apoptosis of activated ras ‐stimulated intestinal epithelial cells

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