Genetic dissection of c-myc apoptotic pathways

Nesbit, Chadd E.; Tersak, Jean M.; Grove, Linette; Drzal, Amy; Choi, Hyun-Jung; Prochownik, Edward V.

doi:10.1038/sj.onc.1203636

Cited by 56 publications

(85 citation statements)

References 59 publications

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“…Growth kinetics in limiting interleukin-3 (IL-3) concentrations (50 pg ml À1 ) were monitored as in (c). (e) Rat1a-GpIba and Rat1a-vector cells were grown to approximately 50% confluency and then deprived of serum (Nesbit et al, 2000). At the times indicated, viable cell counts were determined in triplicate.…”

Section: Gpiba Promotes Growth and Survivalmentioning

confidence: 99%

“…Isolation of RNA was performed as described (Nesbit et al, 2000). Preparation of biotinylated RNA (cRNA) was performed by the PittArray DNA Microarray Facility of the Genomics and Proteomics Core Laboratories at the University of Pittsburgh Medical Center.…”

Section: Dna Microarraysmentioning

confidence: 99%

“…Introduction c-Myc promotes transformation and alterations in proliferation, apoptosis and genomic instability (GI) in association with the deregulation of hundreds of direct target genes (Nesbit et al, 2000;Dang et al, 2006). The degree to which these properties are affected varies according to the levels of c-Myc, the cell type and the expression of other modifying genes (Grandori et al, 2000;Zhou and Hurlin, 2001).…”

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confidence: 99%

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Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

Cohen

et al. 2007

Oncogene

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GpIba, a subunit of the von Willebrand factor receptor, functions during blood clotting to promote platelet adhesion and activation. GpIba is widely expressed, is positively regulated by c-Myc and is essential for the promotion of c-Myc-mediated chromosomal instability. We now show that GpIba is also a classical oncoprotein in which its deregulated expression leads to transformation, reduced growth factor requirements, increased resistance to apoptosis, and, in primary cells, p53-dependent senescence. Finally, GpIba also promotes double-stranded DNA breaks, and induces profound nuclear dysmorphology, indicating that, in addition to its direct transforming function, it displays genotoxicity at several distinct levels. These findings identify novel functions for GpIba and pathways through which c-Myc mediates transformation and global genomic destabilization.

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Section: Gpiba Promotes Growth and Survivalmentioning

confidence: 99%

Section: Dna Microarraysmentioning

confidence: 99%

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confidence: 99%

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Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

Cohen

et al. 2007

Oncogene

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“…We have previously shown that an expressed sequence tag (#697416, Nesbit et al, 2000) is markedly downregulated in 32D cells constitutively expressing high levels of c-Myc. The complete sequence of this EST, obtained in our laboratory, is 100% homologous to the reported sequence of 'onzin', which was independently sequenced and deposited in GenBank (Accession No.…”

Section: Onzin Is Highly Conserved and Its Expression Is Tissue-restrmentioning

confidence: 99%

“…As an alternative for characterizing c-Myc targets, we have utilized the murine 32D myeloid cell line and identified >80 putative c-Myc target genes by transcriptional profiling (Nesbit et al, 2000). Among those so far evaluated are MT-MC1 and CCL6 Yi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt–Mdm2–p53 pathway

et al. 2005

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The c-Myc oncoprotein is a general transcription factor whose target genes dictate the c-Myc phenotype. One such target of c-Myc, 'onzin', is normally expressed at high levels in myeloid cells and is dramatically downregulated in response to c-Myc overexpression. We show here that short hairpin interfering RNA-mediated knockdown of endogenous onzin results in a reduced growth rate and a proapoptotic phenotype. In contrast, onzin overexpression in fibroblasts is associated with an increased growth rate, resistance to apoptotic stimuli, loss of the G2/M checkpoint, and tumorigenic conversion. Onzin-overexpressing cells fail to induce p53 in response to apoptotic stimuli and contain higher levels of the active, phosphorylated forms of Akt1 and, more strikingly, of Mdm2. Using yeast two-hybrid and coimmunoprecipitation assays, we show that onzin directly interacts with both proteins. Green fluorescent protein tagging also confirms directly that Akt1 and Mdm2 colocalize with onzin, although the precise subcellular distribution of each protein is dependent on its relative abundance. Collectively, our results identify onzin as a novel regulator of several p53-dependent aspects of the c-Myc phenotype via its dramatic effect on Mdm2. This is reminiscent of the c-Mycp19 ARF -| Mdm2 pathway and might function as a complementary arm to ensure the proper cellular response to oncogenic and/or apoptotic stimuli.

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Elevated protein expression of cyclin D1 and Fra‐1 but decreased expression of c‐Myc in human colorectal adenocarcinomas overexpressing β‐catenin

Wang

Xiao

et al. 2002

Intl Journal of Cancer

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Mutations of the adenomatous polyposis coli tumor suppressor gene, or its downstream target ␤-catenin, have been implicated in the initiation of most sporadic human colorectal epithelial neoplasms. These mutations, in turn, lead to aberrant nuclear accumulation of ␤-catenin and subsequent activation of the ␤-catenin/Tcf transcription factor complex. In vitro studies utilizing cultured human colon cancer cell lines have identified c-myc, cyclin D1 and fra-1 as target genes of ␤-catenin/Tcf signaling. In our study, 12 cases of human colorectal adenocarcinomas were examined by Western immunoblotting analysis and immunohistochemical staining to specifically investigate whether the protein expression of these target genes was indeed altered in vivo by ␤-catenin dysregulation. The results show that the protein level of ␤-catenin was significantly increased in all 12 tumors (3.4 ؎ 1.0-fold increase compared to the control normal mucosa by Western immunoblotting, p < 0.05), and this increase was associated with positive nuclear staining by immunohistochemistry in 10 cases. Increased levels of expression of cyclin D1 and Fra-1 proteins were also demonstrated in every tumor (9.0 ؎ 2.7 and 3.3 ؎ 0.9-fold increases compared to normal mucosa, respectively). Surprisingly, the protein level of c-Myc was significantly decreased in all tumors examined by 49 ؎ 19% (p < 0.05), but the c-myc mRNA level was increased in 8 of 12 tumors when compared to that in normal mucosa by RT-PCR. Immunohistochemical staining performed on these carcinomas and additional 27 colorectal carcinomas further demonstrated that the protein expression level of c-Myc and ␤-catenin nuclear localization were not correlated. Moreover, 15 of 20 colorectal adenomas exhibited positive nuclear ␤-catenin immunostaining, among which 11 also exhibited increased c-Myc protein expression. These data thus support the notion that upregulation of cyclin D1 and Fra-1 in human colorectal adenocarcinomas is driven by abnormally expressed ␤-catenin. However, the regulation of c-myc expression in colorectal tumors appears to be more complex. While dysregulated ␤-catenin may cause a transcriptional upregulation of the c-myc gene, the c-Myc protein expression appears to be further regulated by a posttranscriptional mechanism(s) during the process of neoplastic progression.

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Genetic dissection of c-myc apoptotic pathways

Cited by 56 publications

References 59 publications

Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

Transformation, genomic instability and senescence mediated by platelet/megakaryocyte glycoprotein Ibα

Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt–Mdm2–p53 pathway

Elevated protein expression of cyclin D1 and Fra‐1 but decreased expression of c‐Myc in human colorectal adenocarcinomas overexpressing β‐catenin

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