Effects of Cyclin D1 Overexpression on G1 Progression-Related Events

Imoto, Masaya; Doki, Yuichiro; Jiang, Wei; Han, E. K.-H.; Weinstein, I. Bernard

doi:10.1006/excr.1997.3713

Cited by 37 publications

(24 citation statements)

References 32 publications

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“…The kinase activity of PERK was shown to be essential for this arrest, strongly implying that eIF2␣ phosphorylation plays a role in this process. Elevated levels of phosphorylated eIF2␣ were subsequently shown to inhibit translation of cyclin D1 (36,60,66). Inducible expression of the eIF2␣-S51D variant in our system may be exerting a similar effect, albeit at low levels since to date we have been unable to demonstrate a significant perturbation of the cell cycle profile in exponentially growing populations of the inducible eIF2␣-S51D-expressing cell lines (data not shown).…”

Section: Discussionmentioning

confidence: 67%

Defects in Translational Regulation Mediated by the α Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

Perkins

Barber

2004

Molecular and Cellular Biology

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Suppression of protein synthesis through phosphorylation of the translation initiation factor ␣ subunit of eukaryotic initiation factor 2 (eIF2␣) is known to occur in response to many forms of cellular stress. To further study this, we have developed novel cell lines that inducibly express FLAG-tagged versions of either the phosphomimetic eIF2␣ variant, eIF2␣-S51D, or the phosphorylation-insensitive eIF2␣-S51A. These variants showed authentic subcellular localization, were incorporated into endogenous ternary complexes, and were able to modulate overall rates of protein synthesis as well as influence cell division. However, phosphorylation of eIF2␣ failed to induce cell death or sensitize cells to killing by proapoptotic stimuli, though it was able to inhibit viral replication, confirming the role of eIF2␣ in host defense. Further, although the eIF2␣-S51A variant has been shown to transform NIH 3T3 cells, it was unable to transform the murine fibroblast 3T3 L1 cell line. To therefore clarify this issue, we explored the role of eIF2␣ in growth control and demonstrated that the eIF2␣-S51A variant is capable of collaborating with hTERT and the simian virus 40 large T antigen in the transformation of primary human kidney cells. Thus, dysregulation of translation initiation is indeed sufficient to cooperate with defined oncogenic elements and participate in the tumorigenesis of human tissue.

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Section: Discussionmentioning

confidence: 67%

Defects in Translational Regulation Mediated by the α Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

Perkins

Barber

2004

Molecular and Cellular Biology

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“…40,41) Furthermore, serum-induced expression of cyclin E is higher in cells constitutively overexpressing cyclin D1. 42) Therefore, the enhancement of cyclin E expression in NIH-PIS cells (Fig. 6C) could be secondary to the increase in cyclin D1.…”

Section: Discussionmentioning

confidence: 89%

Overexpression of Phosphatidylinositol Synthase Enhances Growth and G1 Progression in NIH3T3 cells

Deguchi

Segawa

Hosaka

et al. 2002

Japanese Journal of Cancer Research

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Phosphatidylinositol (PI) turnover is thought to play an important role in the regulation of cell growth. PI synthase (PIS, cytidine diphosphate (CDP)-diacylglycerol (DG): myo-inositol 3-phosphatidyltransferase, EC 2.7.8.11) acts at the last step in the de novo biosynthesis of PI by catalyzing the condensation of CDP-DG and myo-inositol. To study the physiological role of PIS, we established murine NIH3T3 fibroblasts that stably overexpress PIS, by transfection with PIS cDNA (NIH-PIS cells). In immunofluorescence assays, the constitutively overexpressed PIS was found to be localized in the endoplasmic reticulum, as previously reported for the native enzyme activity. NIH-PIS cells showed an increase in PI synthesis in vitro and in vivo, as well as increased cellular levels of PI-4,5-P 2 and PI-3,4,5-P 3 . They also displayed a decrease in their doubling time and accelerated G1 progression. Overexpression of PIS increased cellular levels of the cyclin D1 and E proteins and Akt kinase activity in serum-stimulated quiescent NIH3T3 cells. Moreover, PIS overexpression potentiated the colony formation of NIH3T3 cells in soft agar. These results suggest that PIS accelerates G1 progression and stimulates growth by increasing cellular levels of cyclins D1 and E. Key words: Phosphatidylinositol synthase -Cell cycle -Cyclin D -Cyclin E -AktPhosphatidylinositol (PI) is a minor membrane component representing between 2-12% of the total phospholipids in eukaryotic cells.1) It is a precursor of second messengers, including PI phosphates, inositol-polyphosphates, and diacylglycerol (DG). The hydrolysis of PI-4,5-P 2 (PIP 2 ) by PI-specific phospholipase C (PI-PLC) is often activated when cells are stimulated by various growth factors or hormones. PIP 2 breakdown leads to the generation of two second messengers: inositol-1,4,5-triphosphate (IP 3 ), which is responsible for the release of Ca 2+ from intracellular stores, and DG, which activates several isoforms of protein kinase C.2-5) After receptor-triggered hydrolysis of PIP 2 , PI must be resynthesized in order to maintain a constant level of PI in cell membranes, and this requirement is met by phosphatidylinositol synthase (PIS) activity.PIS (CDP-DG: myo-inositol 3-phosphatidyltransferase, EC 2.7.8.11) acts at the last step in the de novo biosynthesis of PI by catalyzing the condensation of CDP-DG and myo-inositol. PIS appears to be located primarily on the cytoplasmic aspect of the endoplasmic reticulum, [6][7][8] and its enzyme activity is detected in plasma membrane preparations. [9][10][11][12] In yeast, Nikawa et al. reported that disruption of the PIS gene is lethal. Nonviable spores were observed with characteristic terminal phenotypes, suggesting that the PIS gene is essential for progression of the yeast cell cycle. 13)The rat PIS cDNA has been cloned by functional complementation of a Saccharomyces cerevisiae PIS mutant deficient in PIS activity.14) The cloned cDNA encodes a protein of 213 amino acids with a calculated molecular weight of 23 613 Da. Lykidis et al. ...

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“…Overexpression of cyclin Dl can shorten the Gl cell cycle phase, decrease cell size, reduce requirements for growth factors (38)(39)(40). Microinjection of antisense constructs or antibodies to cyclin Dl into normal fibroblasts can prevent them from entering S phase (38,41).…”

Section: Discussionmentioning

confidence: 99%

Role of IGFBP-3/IGFBP-3 Receptor Interaction in Normal and Malignant Mammary Growth: A Potential Diagnostic Parameter and New Strategy for Endocrine Therapy

Oh¹

2000

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SUPPLEMENTARY NOTES 12a. DISTRIBUTION /AVAILABILITY STATEMENTApproved for public release; distribution unlimited 12b. DISTRIBUTION CODE 13. ABSTRACT: The proposal of my grant is to investigate the biological significance and mechanism of insulin-like growth factor binding protein-3 (IGFBP-3) as well as identification and characterization of the IGFBP-3 receptor in human breast cancer cells.As a third year task, we have successfully characterized binding specificity of the IGFBP-3 receptor to IGFBP-3. It revealed that only IGFBP-3 and its fragment (aa88-148) bind the IGFBP-3 receptor with high affinity, whereas IGFBPs, -2, 4-, -5 and -6 did not interact with the IGFBP-3 receptor, demonstrating specificity of the IGFBP-3 receptor. We have also identified the IGFBP-3/IGFBP-3 receptor-mediated signal transduction pathway in human breast cancer cells. Current studies demonstrated that the IGFBP-3/IGFBP-3 receptor axis causes cell cycle arrest in Gl phase and induces apoptosis. The underlying mechanisms are ablation of MAPK signaling cascades and increase of caspase activity, respectively. Further through investigation is currently in the process in my laboratory. As characterization of the structure-functional analysis of IGFBP-3 and the IGFBP-3 receptor, we identified differential effects of IGFBP-3 and those IGFBP-3 proteolytic fragments on ligand binding, cell surface association and IGF-I receptor signaling. Current findings under this grant support will provide pivotal evidence for clinical significance and potential application of the IGFBP-3/IGFBP-3 receptor axis in the prevention and/or treatment of human neoplasia, in particular, breast cancer. I. SUBJECT TERMS Breast Cancer INTRODUCTION.The insulin-like growth factor binding proteins (IGFBPs) 1-6 bind IGF-I and IGF-II with high affinity and serve to transport the IGFs, prolong their half-lives, and modulate their proliferative and anabolic effects on target cells. The molecular mechanisms involved in the interaction of the IGFBPs with the IGFs and their receptors remain unclear, but these molecules appear, at least, to regulate the availability of free IGFs for interaction with IGF receptors.Recent studies from our laboratory and others demonstrated that some IGFBPs have ability to exert IGF-independent actions.In this project, I proposed investigation of the characterization of the IGFBP-3-specific receptor, the elucidation of the pertinent signal transduction pathways and analysis of structure-function relationships in the IGFBP-3 in the context of growth control in human breast cancer.II. BODY. I. characterization of the IGFBP-3 receptor in human breast cancer cells (Tasks 1-7).In our continuing investigation of the biological importance of IGFBP-3, we are characterizing specificity of the IGFBP-3 receptor binding to IGFBP-3 and involvement of the IGFBP-3 receptor on the IGFBP-3-induced growth inhibition. As IGFBP-3 has been previously reported to specifically bind to the surface of breast cancer cells and subsequently exhibit growth suppressing activ...

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Effects of Cyclin D1 Overexpression on G1 Progression-Related Events

Cited by 37 publications

References 32 publications

Defects in Translational Regulation Mediated by the α Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

Defects in Translational Regulation Mediated by the α Subunit of Eukaryotic Initiation Factor 2 Inhibit Antiviral Activity and Facilitate the Malignant Transformation of Human Fibroblasts

Overexpression of Phosphatidylinositol Synthase Enhances Growth and G1 Progression in NIH3T3 cells

Role of IGFBP-3/IGFBP-3 Receptor Interaction in Normal and Malignant Mammary Growth: A Potential Diagnostic Parameter and New Strategy for Endocrine Therapy

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