Guanine Nucleotide Exchange Factor, Tiam1, Directly Binds to c-Myc and Interferes with c-Myc-mediated Apoptosis in Rat-1 Fibroblasts

Otsuki, Yoshiro; Tanaka, Masamitsu; Kamo, Takaharu; Kitanaka, Chifumi; Kuchino, Yoshiyuki; Sugimura, Haruhiko

doi:10.1074/jbc.m206733200

Cited by 31 publications

(18 citation statements)

References 46 publications

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“…It remains possible however that identification of E2 target genes at earlier time points may reveal enrichment in c-Myc-binding sites, since MYC is one of the earliest known estrogen target genes (82). Of interest, TIAM1, a repressor of c-Myc that prevents its apoptotic effects (83), is also a primary estrogen target gene and may limit the duration of the induction of some c-Myc target genes.…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells

Bourdeau

Deschênes

Laperrière

et al. 2007

Nucleic Acids Research

105

110

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Estrogen receptors (ERs), which mediate the proliferative action of estrogens in breast cancer cells, are ligand-dependent transcription factors that regulate expression of their primary target genes through several mechanisms. In addition to direct binding to cognate DNA sequences, ERs can be recruited to DNA through other transcription factors (tethering), or affect gene transcription through modulation of signaling cascades by non-genomic mechanisms of action. To better characterize the mechanisms of gene regulation by estrogens, we have identified more than 700 putative primary and about 1300 putative secondary target genes of estradiol in MCF-7 cells through microarray analysis performed in the presence or absence of the translation inhibitor cycloheximide. Although siRNA-mediated inhibition of ERα expression antagonized the effects of estradiol on up- and down-regulated primary target genes, estrogen response elements (EREs) were enriched only in the vicinity of up-regulated genes. Binding sites for several other transcription factors, including proteins known to tether ERα, were enriched in up- and/or down-regulated primary targets. Secondary estrogen targets were particularly enriched in sites for E2F family members, several of which were transcriptionally regulated by estradiol, consistent with a major role of these factors in mediating the effects of estrogens on gene expression and cellular growth.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells

Bourdeau

Deschênes

Laperrière

et al. 2007

Nucleic Acids Research

105

110

View full text Add to dashboard Cite

show abstract

“…We offer the following explanations. First, it is likely that Tiam1, by itself, or Tiam1-activated Rac1 might control activities of putative transcriptional factors that might play negative modulatory roles in GSIS; regulation of cellular function by such factors [e.g., STAT and c-myc] has been described in other cell types [54, 55]. This needs to be verified in the β-cell.…”

Section: Discussionmentioning

confidence: 99%

Regulatory roles for Tiam1, a guanine nucleotide exchange factor for Rac1, in glucose-stimulated insulin secretion in pancreatic β-cells

Veluthakal

Madathilparambil

McDonald

et al. 2009

Biochemical Pharmacology

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Using various biochemical, pharmacological and molecular biological approaches, we have recently reported regulatory roles for Rac1, a small G-protein, in glucose-stimulated insulin secretion [GSIS]. However, little is understood with respect to localization of, and regulation by, specific regulatory factors of Rac1 in GSIS. Herein, we investigated regulatory roles for Tiam1, a specific nucleotide exchange factor [GEF] for Rac1, in GSIS in pancreatic β-cells. Western blot analysis indicated that Tiam1 is predominantly cytosolic in distribution. NSC23766, a specific inhibitor of Tiam1-mediated activation of Rac1, markedly attenuated glucose-, but not KCl-induced insulin secretion in INS 832/13 cells and normal rat islets. Further, NSC23766 significantly reduced glucose-induced activation [i.e., GTP-bound form] and membrane association of Rac1 in INS 832/13 cells and rat islets. Moreover, siRNA-mediated knock-down of Tiam1 markedly inhibited glucose-induced membrane trafficking and activation of Rac1 in INS 832/13 cells. Interestingly, however, in contrast to the inhibitory effects of NSC23766, Tiam1 gene depletion potentiated GSIS in these cells; such a potentiation of GSIS was sensitive to extracellular calcium. Together, our studies present the first evidence for a regulatory role for Tiam1/Rac1-sensitive signaling step in GSIS. They also provide evidence for the existence of a potential Rac1/Tiam1-independent, but calcium-sensitive component for GSIS in these cells.

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“…A final, rather awkward binding partner of Tiam1 is the oncogene c‐Myc [44]. This interaction was reported to be dependent on the Myc‐box II domain of c‐Myc and to require the N‐terminus (upstream of the PHn domain) of Tiam1.…”

Section: Regulation Of Signalling Through Protein–protein Interactionsmentioning

confidence: 99%

Regulation of Tiam1–Rac signalling

2003

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The GTPases of the Rho family are molecular switches that play an important role in a wide range of cellular processes and are increasingly implicated in tumourigenesis. Unlike what was found for the Ras oncogenes in tumours, hardly any activating mutations have been found in the genes encoding Rho proteins. In the past, we have identi¢ed Tiam1 (T-lymphoma invasion and metastasis) as a speci¢c activator for the Rholike GTPase Rac. In vivo, Tiam1 de¢ciency protects against Ras-induced skin carcinogenesis, underscoring the consequences of deregulated signalling for the onset and progression of tumours. Thus, an important level of regulation of signalling via the Rho-like GTPases comes from the speci¢c control of their activators. In this paper, we review what is known on the speci¢c regulation of Tiam1 signalling towards Rac.

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Guanine Nucleotide Exchange Factor, Tiam1, Directly Binds to c-Myc and Interferes with c-Myc-mediated Apoptosis in Rat-1 Fibroblasts

Cited by 31 publications

References 46 publications

Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells

Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells

Regulatory roles for Tiam1, a guanine nucleotide exchange factor for Rac1, in glucose-stimulated insulin secretion in pancreatic β-cells

Regulation of Tiam1–Rac signalling

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