Overexpression of Insulin-like Growth Factor Binding Protein-3 by Senescent Human Fibroblasts: Attenuation of the Mitogenic Response to IGF-I

Grigoriev, Vitalii G.; Moerman, Elena J.; Goldstein, Samuel

doi:10.1006/excr.1995.1234

Cited by 27 publications

(13 citation statements)

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“…Large amounts of IGFBP3 in old cells might block or reduce IGF-1 action through IGF receptors, resulting in attenuation of the mitogenic effect of IGF-1 (Goldstein et al ., 1991;Grigoriev et al ., 1995). Therefore, the overexpression of IGFBP3 might induce senescence via a concerted antiproliferative effect by interrupting the IGF pathway.…”

Section: Discussionmentioning

confidence: 99%

Regulation of replicative senescence by insulin‐like growth factor‐binding protein 3 in human umbilical vein endothelial cells

Kim

Seu

et al. 2007

Aging Cell

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SummaryInsulin/insulin-like growth factor (IGF) signaling pathways are among the most conserved processes in aging in organisms ranging from yeast to mammals. Previously, using cDNA microarray technology, we reported that expression of IGF-binding protein 3 (IGFBP3), one of the IGF-binding proteins, was increased with age in human dermal fibroblasts. In this study, the role of IGFBP3 on cellular senescence was studied in human umbilical vein endothelial cells (

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Section: Discussionmentioning

confidence: 99%

Regulation of replicative senescence by insulin‐like growth factor‐binding protein 3 in human umbilical vein endothelial cells

Kim

Seu

et al. 2007

Aging Cell

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“…Both growth stimulatory and inhibitory functions of IGFBP-3 have been described in an IGF-dependent or -independent manner (17). IGFBP-3 has been implicated in cellular senescence (19,22). IGFBP-3 was induced in primary and immortalized human esophageal cells within 24 h upon growth factor deprivation while a concomitant reduction in cell proliferation was observed (Table 2 and data not shown).…”

Section: Igfbp-3 Prevents Igf-ir Activation By Igf-i In Esophageal Epmentioning

confidence: 98%

EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I

Takaoka¹,

Smith²,

Mashiba³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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IGF and EGF regulate various physiological and pathological processes. IGF binding protein (IGFBP)-3 regulates cell proliferation in IGF-dependent and -independent fashions. Recently, we identified IGFBP-3 as a novel EGF receptor (EGFR) downstream target molecule in primary and immortalized human esophageal epithelial cells, suggesting an interplay between the EGF and IGF signaling pathways. However, the regulatory mechanisms for IGFBP-3 expression and its functional role in esophageal cell proliferation remain to be elucidated. Herein, we report that IGFBP-3 mRNA and protein were induced upon growth factor deprivation in primary and immortalized human esophageal cells through mechanisms requiring p53-independent de novo mRNA transcription and protein synthesis. This occurred in the face of the activated phosphatidylinositol 3-OH-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. Secreted IGFBP-3 neutralized IGFs and prevented IGF-I receptor (IGF-IR) activation. In contrast, EGF suppressed IGFBP-3 mRNA and protein expression through activation of MAPK in an EGFR-tyrosine kinase-dependent manner to restore the cellular response to IGF-I. When stably overexpressed, wild-type IGFBP-3 but not I56G/L80G/L81G (GGG) mutant IGFBP-3, which has a reduced affinity to IGFs, prevented IGF-I from activating IGF-IR and Akt as well as stimulating cell proliferation. However, unlike other cell types where IGFBP-3 exerts antiproliferative effects, neither wild-type nor GGG mutant IGFBP-3 alone affected cell proliferation or EGFR activity. These results indicate that IGF signaling is subject to negative regulation through IGFBP-3 and positive regulation by EGF, the latter of which suppresses IGFBP-3. This provides a platform for understanding the novel cross talk between EGF- and IGF-mediated pathways.

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“…Thus, expression of early-growth response genes, e.g., the c-fos gene, cannot be induced by serum growth factors in senescent cells (73). Furthermore, insulin-like growth factor binding protein 3 (IGFBP-3), a member of a protein family that regulates the mitogenic activity of IGF-I (for a review, see reference 11), is strongly overexpressed in senescent cells (30,31,55). IGFBP-3 can block the proliferation of various cell types in vitro (for a review, see reference 59) by at least two distinct ways.…”

mentioning

confidence: 99%

Human Papillomavirus Type 16 E7 Oncoprotein Binds and Inactivates Growth-Inhibitory Insulin-Like Growth Factor Binding Protein 3

Mannhardt

Weinzimer

Wagner

et al. 2000

Molecular and Cellular Biology

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The E7 protein encoded by human papillomavirus type 16 is one of the few viral genes that can immortalize primary human cells and thereby override cellular senescence. While it is generally assumed that this property of E7 depends on its interaction with regulators of the cell cycle, we show here that E7 targets insulin-like growth factor binding protein 3 (IGFBP-3), the product of a p53-inducible gene that is overexpressed in senescent cells. IGFBP-3 can suppress cell proliferation and induce apoptosis; we show here that IGFBP-3-mediated apoptosis is inhibited by E7, which binds to IGFBP-3 and triggers its proteolytic cleavage. Two transformation-deficient mutants of E7 failed to inactivate IGFBP-3, suggesting that inactivation of IGFBP-3 may contribute to cell transformation.Human papillomaviruses (HPVs) of the high-risk group (e.g., HPV-16) cause cancers in humans, while papillomaviruses of the low-risk group (e.g., HPV-11) cause benign epithelial hyperproliferation (90). Cell transformation by highrisk HPVs requires expression of the viral genes E6 and E7 (for a review, see reference 1). Coexpression of HPV-16 E6 and E7 is sufficient to immortalize primary human keratinocytes (35, 57), the natural host cells for papillomavirus infection. The E6 protein of HPV-16 interacts with the p53 tumor suppressor, which leads to recruitment of the ubiquitin ligase E6AP (39), resulting in the ubiquitination and subsequent degradation of p53 (72). Consequently, p53-dependent upregulation of growth-inhibitory genes, such as p21WAF-1 (27), is abrogated. A major target for the E7 oncoprotein of HPV-16 appears to be the p16/Rb pathway, as it is known that E7 binds to all three members of the retinoblastoma protein family and abrogates their growth-suppressive function (for a review, see reference 83); consequently, E7-expressing cells are refractory to growth inhibition by the cyclin-dependent kinase (cdk) inhibitor p16INK4 (49, 50). The identification of specific target proteins for E6 and E7 suggests that both viral oncoproteins target nonidentical regulatory pathways and that immortalization depends on the combined action of both gene products. However, it is known that expression of E7 alone is sufficient to immortalize human cells (85), albeit at reduced efficiency, compared to the simultaneous expression of both E6 and E7 (35). This indicates that E7 may also impinge on growth regulatory pathways that are principal targets for E6. In support of this hypothesis, it was shown that E7 binds and inactivates the cdk inhibitor p21WAF-1 (28, 42), which is encoded by a p53-inducible gene (27). This observation provides an explanation for how p53-mediated growth arrest can be undermined by E7 in the absence of E6, i.e., in cells where p53 is present and functional.Immortalization of mammalian cells is considered the first step in tumorigenesis (88) which abrogates a cellular senescence program that is characterized by irreversible cell cycle exit after extended passaging. There is evidence that mitogenic signal transduction is ...

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Overexpression of Insulin-like Growth Factor Binding Protein-3 by Senescent Human Fibroblasts: Attenuation of the Mitogenic Response to IGF-I

Cited by 27 publications

References 0 publications

Regulation of replicative senescence by insulin‐like growth factor‐binding protein 3 in human umbilical vein endothelial cells

Regulation of replicative senescence by insulin‐like growth factor‐binding protein 3 in human umbilical vein endothelial cells

EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I

Human Papillomavirus Type 16 E7 Oncoprotein Binds and Inactivates Growth-Inhibitory Insulin-Like Growth Factor Binding Protein 3

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