Growth factors as transforming proteins

Heldin, Carl‐Henrik; Westermark, Bengt

doi:10.1007/978-3-642-75189-9_8

Cited by 15 publications

(18 citation statements)

References 184 publications

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“…Therefore, it is conceivable that RasC40-dependent signals impinge selectively upon Pax-8 expression and/or activity. The e ects of Ras transformation on Pax-8 expression have not yet been reported, although reduced levels of Pax-8 expression have been observed in follicular adenomas (Heldin and Westermark, 1991) and in thyroid cells expressing mutated p53 (Battista et al, 1995). RasC40-dependent signals might also downregulate the expression and/or activity of a recently described novel thyroid transcription factor involved in the regulation of NIS expression (Ohmori et al, 1998), or could a ect NIS activity through a post-transcriptional mechanism similar to that observed for TSH (Kaminsky et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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Hormones are specialized mitogens that stimulate proliferation in their di erentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroidspeci®c gene expression. The mitogenic e ects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid di erentiation. However, expression of activated Ras extinguishes the di erentiated phenotype of thyroid cells. One explanation for this apparent paradox is the selective utilization of Ras e ector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic e ects of TSH in cells which retain their di erentiated character. Expression of a Ras e ector mutant (RasV12S35) that signals preferentially through Raf-1, although su cient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter. In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked e ects on thyroid-speci®c gene expression. Unlike the inhibitory e ects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic e ects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in di erentiated cells. Oncogene (2000) 19, 924 ± 932.

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Section: Discussionmentioning

confidence: 99%

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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“…13 Polypeptide growth factors activate growthpromoting pathways to induce cell proliferation. They have been implicated in the multistep pathway of tumorigenesis [14][15][16] and may play a role in pituitary neoplasia. 17 Ligand binding with resultant EGFR activation is thought to be the most important step in the signal transduction pathway.…”

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confidence: 99%

Analysis of epidermal growth factor receptor and activated epidermal growth factor receptor expression in pituitary adenomas and carcinomas

et al. 2004

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Epidermal growth factor receptor plays an important role in the pathogenesis of many malignancies. Various growth factors, including epidermal growth factor receptor, have been shown to influence pituitary tumor growth and differentiation. To analyze the role of epidermal growth factor receptor in pituitary tumor development, we examined normal pituitaries (n ¼ 8), pituitary adenomas (n ¼ 158), and pituitary carcinomas (n ¼ 7) for expression of epidermal growth factor receptor protein and messenger RNA using tissue microarrays and RT-PCR. We also examined (a) the expression of phospho-epidermal growth factor receptor, the activated form of epidermal growth factor receptor, in pituitary tumors and normal pituitaries by immunohistochemistry and (b) the effects on epidermal growth factor receptor expression of treating pituitary cells (HP75 cell line) with epidermal growth factor. Epidermal growth factor receptor and the phosphorylated variant expression were present in normal pituitary cells. Epidermal growth factor receptor messenger RNA was also detected in normal pituitaries, pituitary adenomas, and carcinomas by in situ hybridization and RT-PCR. Most pituitary adenomas showed expression of epidermal growth factor receptor and the phosphorylated variant. Nonfunctional adenomas showed higher levels of expression of epidermal growth factor receptor (76 vs 34%) and of phosphoepidermal growth factor receptor (26 vs 8%) as compared to functional adenomas. Five of seven pituitary carcinomas showed strong expression of both epidermal growth factor receptor and phospho-epidermal growth factor receptor. When a human pituitary cell line (HP75) was cultured in the presence of epidermal growth factor receptor, there was an increase in the levels of both epidermal growth factor receptor and phospho-epidermal growth factor receptor after 5 h of treatment, thus confirming that epidermal growth factor receptor signaling was active in pituitary tumors. These results indicate that activated epidermal growth factor receptor is expressed in pituitary adenomas and carcinomas. Higher levels in pituitary carcinomas suggest a role in pituitary tumor progression.

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“…W natural serum 1; X serum 1 with addition of E 7-21 ; A natural serum 2; B serum 2 with addition of E [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] . % B ¼ percent bound.…”

Section: European Journal Of Endocrinology (1997) 137mentioning

confidence: 99%

“…Although IGF-I is known to be the most important postnatal growth factor (10,11), circulating IGF-II levels in adult humans are higher than the equivalent IGF-I levels presumably originating from the P1 promoter in the liver (12). High IGF-II mRNA expression, especially in sarcomas and some common tumors in children such as Wilms' tumors (13), is evidence for an auto/paracrine function of IGF-II during malignant transformation and tumor development (14)(15)(16)(17)(18). We recently showed that IGF-II is synthesized and released by Wilms' tumor tissue in vitro to a higher extent than in kidneys (19,20).…”

Section: Introductionmentioning

confidence: 99%

“…To sum up, 'big-IGF-II' of different molecular weights has been found in normal tissue, serum (27) or spinal fluid (28) and has also been isolated from tumor cell cultures in vitro, such as a colon carcinoma cell line (29), a teratocarcinoma cell line (30) or a rhabdomyosarcoma cell line (31), with molecular masses ranging from 10 to 16 kDa. Therefore we set out to measure pro-IGF-II, produced by Wilms' tumor cells and secreted into the medium, by a newly developed radioimmunoassay using an antibody directed against amino acids 7-21 of the E-domain of pro-IGF-II (E [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] ) and to determine the molecular weights of various pro-IGF-II forms by gel electrophoresis and immunoblotting with this antibody. prestained molecular weight standards and the goat antirabbit IgG-AP Immun-Lite Chemiluminescent Assay Kit were from Bio-Rad (Hercules, CA, USA).…”

Section: Introductionmentioning

confidence: 99%

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High molecular weight forms of IGF-II ('big-IGF-II') released by Wilms' tumor cells

Schmitt

Ren-Qiu²,

Torresani³

et al. 1997

European Journal of Endocrinology

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Insulin-like growth factor-II (IGF-II) is thought to play a critical role in the development of embryonic tumors such as Wilms' tumor. However, despite highly elevated IGF-II mRNA levels in tumors, IGF-II is not elevated in the serum of patients with Wilms' tumors. Recently high molecular weight forms of IGF-II ('big'-or pro-IGF-II) have been found to be produced by some tumors. In order to prove whether or not high molecular weight forms of IGF-II are produced by Wilms' tumor cells and secreted into the culture medium, we established Wilms' tumor cell lines. After column chromatography of the culture medium, IGF-II and pro-IGF-II concentrations were measured. For pro-IGF-II measurement we established a pro-IGF-II RIA using a rabbit polyclonal antiserum directed against amino acids 7-21 (E 7-21 ) of the E-domain of pro-IGF-II. Gel electrophoresis and Western blotting with anti-IGF-II antibodies revealed a band at 7.5 kDa corresponding to fully processed IGF-II and bands between 10 and 20 kDa. Using pro-IGF-II antiserum, bands between 10 and 25 kDa were detected. We conclude that in vitro cultured Wilms' tumor cells produce and release various forms of 'big IGF-II' with molecular masses between 10 and 25 kDa. It remains uncertain whether these high molecular weight forms of IGF-II represent normal precursors of IGF-II or incorrectly processed IGF-II.

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Growth factors as transforming proteins

Cited by 15 publications

References 184 publications

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Analysis of epidermal growth factor receptor and activated epidermal growth factor receptor expression in pituitary adenomas and carcinomas

High molecular weight forms of IGF-II ('big-IGF-II') released by Wilms' tumor cells

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