Insulin-like Growth Factor-I Receptor (IGF-IR) Translocates to Nucleus and Autoregulates IGF-IR Gene Expression in Breast Cancer Cells

Sarfstein, Rive; Pasmanik‐Chor, Metsada; Yeheskel, Adva; Edry, Liat; Shomron, Noam; Warman, Naama; Wertheimer, Ernst; Maor, Sharon; Shochat, L.; Werner, Haim

doi:10.1074/jbc.m111.281782

Cited by 77 publications

(85 citation statements)

References 53 publications

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“…6(3): 247-254 ________________________________________________________________________________________________________ 251 endothelial cells, as reported previously for other cancers in dogs (Buishand et al, 2012;Maniscalco et al, 2014). In carcinomas, a portion of thyroid follicular cells had positive immunolabeling for nuclear IGF-1R, which is consistent with the findings of Sarfstein et al (2012), who described the translocation of IGF-1R to the nucleus in breast cancer cells and identified a novel mechanism of IGF-1R gene autoregulation. In the present study, IGF-1 and IGF-1R labelling intensity was higher in fibroblasts and endothelial cells of compact carcinoma than in those of healthy thyroid tissues, while follicular-compact carcinoma had intermediate labelling intensity.…”

Section: Discussionmentioning

confidence: 95%

Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

Pessina¹,

Castillo²,

César³

et al. 2017

Open Vet J.

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Immunohistochemical markers (IGF-1, IGF-1R, VEGF, FGF-2, RARα and RXR) were evaluated in healthy canine thyroid glands (n=8) and in follicular-compact (n=8) and compact thyroid carcinomas (n=8). IGF-1, IGF-1R and VEGF expression was higher in fibroblasts and endothelial cells of compact carcinoma than in healthy glands (P < 0.05). Compared to follicular-compact carcinoma, compact carcinoma had higher IGF-1R expression in fibroblasts, and higher FGF-2 expression in endothelial cells (P < 0.05). RARα expression was higher in endothelial cells of compact carcinoma than in those of other groups (P < 0.05). The upregulation of these proliferation-and angiogenesisrelated factors in endothelial cells and/or fibroblasts and not in follicular cells of compact carcinoma compared to healthy glands supports the relevance of stromal cells in cancer progression.

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Section: Discussionmentioning

confidence: 95%

Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

Pessina¹,

Castillo²,

César³

et al. 2017

Open Vet J.

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“…In consistence with our finding, Zhang et al (2015) showed that co‐expression of IGF‐1R containing SUMOylation site mutations (i.e., K1025R and K1100R) substantially decreased proliferation in acute myeloid leukemia cells. Furthermore, a correlation between estrogen receptor positive breast cancer cells and SUMOylated IGF‐1R in cell nuclei was demonstrated by Sarfstein et al (2012). …”

Section: Discussionmentioning

confidence: 84%

SUMO‐modified insulin‐like growth factor 1 receptor (IGF‐1R) increases cell cycle progression and cell proliferation

Lin

Liu

Waraky

et al. 2017

Journal Cellular Physiology

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Increasing number of studies have shown nuclear localization of the insulin‐like growth factor 1 receptor (nIGF‐1R) in tumor cells and its links to adverse clinical outcome in various cancers. Any obvious cell physiological roles of nIGF‐1R have, however, still not been disclosed. Previously, we reported that IGF‐1R translocates to cell nucleus and modulates gene expression by binding to enhancers, provided that the receptor is SUMOylated. In this study, we constructed stable transfectants of wild type IGF1R (WT) and triple‐SUMO‐site‐mutated IGF1R (TSM) using igf1r knockout mouse fibroblasts (R‐). Cell clones (R‐WT and R‐TSM) expressing equal amounts of IGF‐1R were selected for experiments. Phosphorylation of IGF‐1R, Akt, and Erk upon IGF‐1 stimulation was equal in R‐WT and R‐TSM. WT was confirmed to enter nuclei. TSM did also undergo nuclear translocation, although to a lesser extent. This may be explained by that TSM heterodimerizes with insulin receptor, which is known to translocate to cell nuclei. R‐WT proliferated substantially faster than R‐TSM, which did not differ significantly from the empty vector control. Upon IGF‐1 stimulation G1‐S‐phase progression of R‐WT increased from 12 to 38%, compared to 13 to 20% of R‐TSM. The G1‐S progression of R‐WT correlated with increased expression of cyclin D1, A, and CDK2, as well as downregulation of p27. This suggests that SUMO‐IGF‐1R affects upstream mechanisms that control and coordinate expression of cell cycle regulators. Further studies to identify such SUMO‐IGF‐1R dependent mechanisms seem important.

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“…Previous studies have revealed that IGF1R is sumoylated and translocated to the nucleus, which permits the receptor to interact with chromatin, and function as a transcriptional regulator (95)(96)(97). Nuclear IGF1R specifically binds to and functions as a transcriptional activator of its own promoter, and interferes with signaling pathways (98). Specifically, nuclear IGF1R interferes with Wnt signaling, which upregulates ABC drug transporters and modulates drug responses (99).…”

Section: Interacting With Ecmmentioning

confidence: 99%

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

et al. 2017

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Abstract. Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options.

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Insulin-like Growth Factor-I Receptor (IGF-IR) Translocates to Nucleus and Autoregulates IGF-IR Gene Expression in Breast Cancer Cells

Cited by 77 publications

References 53 publications

Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

SUMO‐modified insulin‐like growth factor 1 receptor (IGF‐1R) increases cell cycle progression and cell proliferation

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

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