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Query: UNIPROT:P06889 (Mol)
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Although several genes involved in mitochondrial function are direct Myc targets, the role of Myc in mitochondrial biogenesis has not been directly established. We determined the effects of ectopic Myc expression or the loss of Myc on mitochondrial biogenesis. Induction of Myc in P493-6 cells resulted in increased oxygen consumption and mitochondrial mass and function. Conversely, compared to wild-type Myc fibroblasts, Myc null rat fibroblasts have diminished mitochondrial mass and decreased number of normal mitochondria. Reconstitution of Myc expression in Myc null fibroblasts partially restored mitochondrial mass and function and normal-appearing mitochondria. Concordantly, we also observed in primary hepatocytes that acute deletion of floxed murine Myc by Cre recombinase resulted in diminished mitochondrial mass in primary hepatocytes. Our microarray analysis of genes responsive to Myc in human P493-6 B lymphocytes supports a role for Myc in mitochondrial biogenesis, since genes involved in mitochondrial structure and function are overrepresented among the Myc-induced genes. In addition to the known direct binding of Myc to many genes involved in mitochondrial structure and function, we found that Myc binds the TFAM gene, which encodes a key transcriptional regulator and mitochondrial DNA replication factor, both in P493-6 lymphocytes with high ectopic MYC expression and in serum-stimulated primary human 2091 fibroblasts with induced endogenous MYC. These observations support a pivotal role for Myc in regulating mitochondrial biogenesis.
Mol Cell Biol 2005 Jul
PMID:Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. 1598 31

Many subtypes of B-cell malignancy are characterized by chromosomal translocations that target the immunoglobulin loci. Molecular cloning of such translocations continues to allow the identification of genes whose deregulated expression plays a pivotal role in the pathogenesis of B-cell malignancy. The clustering of breakpoints within the immunoglobulin loci has allowed the development of rapid and robust polymerase chain reaction methods for cloning. We discuss in this chapter the use of long-distance inverse polymerase chain reaction methods to clone immunoglobulin chromosomal translocation breakpoints from clinical material. These methods have been successfully applied to several other types of chromosomal translocation including those involving other genes such as BCL6, ETV6, and MYC.
Methods Mol Med 2005
PMID:Cloning of immunoglobulin chromosomal translocations by long-distance inverse polymerase chain reaction. 1599 70

The enzyme telomerase catalyzes the de novo synthesis of telomere repeats, thereby maintaining telomere length, which is necessary for unlimited cellular proliferation. Telomerase reverse transcriptase (TERT), the catalytic domain of telomerase, is the rate-limiting factor for telomerase activity and is expressed in virtually all tumors. Thus, TERT has been proposed as a marker with diagnostic and prognostic potential in breast cancer as well as a basis for breast cancer therapeutics. In these contexts, it is important to define the sites and extent of TERT expression in normal and cancerous human breast tissues. In this study, levels of TERT mRNA were measured within a set of 36 breast carcinomas and 5 normal breast samples by quantitative real-time reverse transcription-PCR, and we subsequently identified and characterized the cells expressing TERT mRNA within these tissues using in situ hybridization. The results show that (a) detectable TERT mRNA expression is specific to the epithelial cells; (b) TERT is expressed in both normal and malignant breast tissues; (c) the pattern and level of TERT expression are heterogeneous, with approximately 75% of tumors expressing bulk TERT mRNA levels equal to or less than those within normal breast tissue; and (d) tumors expressing above-normal levels of TERT mRNA are more likely to be histopathologic grade 3 (P = 0.002), contain high fraction of cells in S phase (P = 0.004), and have increased levels of MYC mRNA (P = 0.034).
Mol Cancer Res 2005 Sep
PMID:Quantitative and spatial measurements of telomerase reverse transcriptase expression within normal and malignant human breast tissues. 1617 97

The c-myc proto-oncogene encodes a nuclear protein that is deregulated and/or mutated in most human cancers. Acting primarily as an activator and sometimes as a repressor, MYC protein controls the synthesis of up to 10-15% of genes. The key MYC targets contributing to oncogenesis are incompletely enumerated and it is not known whether pathology arises from the expression of physiologic targets at abnormal levels or from the pathologic response of new target genes that are not normally regulated by MYC. Regardless of which, available evidence indicates that the level of MYC expression is an important determinant of MYC biology. The c-myc promoter has architectural and functional features that contribute to uniform expression and help to prevent or mitigate conditions that might otherwise create noisy expression. Those features include the use of an expanded proximal promoter, the averaging of input from dozens of transcription factors, and real-time feedback using the supercoil-deformable Far UpStream Element (FUSE) as physical sensor of ongoing transcriptional activity, and the FUSE binding protein (FBP) as well as the FBP interacting repressor (FIR) as effectors to enforce normal transcription from the c-myc promoter.
Mol Cells 2005 Oct 31
PMID:c-myc expression: keep the noise down! 1626 88

Double minutes (dmin)-circular, extra-chromosomal amplifications of specific acentric DNA fragments-are relatively frequent in malignant disorders, particularly in solid tumors. In acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), dmin are observed in approximately 1% of the cases. Most of them consist of an amplified segment from chromosome band 8q24, always including the MYC gene. Besides this information, little is known about their internal structure. We have characterized in detail the genomic organization of 32 AML and two MDS cases with MYC-containing dmin. The minimally amplified region was shown to be 4.26 Mb in size, harboring five known genes, with the proximal and the distal amplicon breakpoints clustering in two regions of approximately 500 and 600 kb, respectively. Interestingly, in 23 (68%) of the studied cases, the amplified region was deleted in one of the chromosome 8 homologs at 8q24, suggesting excision of a DNA segment from the original chromosomal location according to the 'episome model'. In one case, sequencing of both the dmin and del(8q) junctions was achieved and provided definitive evidence in favor of the episome model for the formation of dmin. Expression status of the TRIB1 and MYC genes, encompassed by the minimally amplified region, was assessed by northern blot analysis. The TRIB1 gene was found over-expressed in only a subset of the AML/MDS cases, whereas MYC, contrary to expectations, was always silent. The present study, therefore, strongly suggests that MYC is not the target gene of the 8q24 amplifications.
Hum Mol Genet 2006 Mar 15
PMID:MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene. 1645 26

2,4,6-Triiodophenol (Bobel-24, AM-24) was originally described as a nonsteroid antiinflammatory molecule. We have synthesized three derivatives of Bobel-24 (Bobel-4, Bobel-16, and Bobel-30) and tested their activities as putative antileukemic agents. We have found that Bobel-24 and Bobel-16 were dual inhibitors of cyclooxygenase and 5-lipoxygenase, whereas Bobel-4 and Bobel-30 were selective against 5-lipoxygenase. We have tested the antiproliferative activity of these compounds on a panel of cell lines derived from myeloid and lymphoid leukemias (K562, Raji, HL-60, and Molt4). The cytotoxic IC(50) in these cell lines ranged between 14 and 50 micromol/L, but it was higher for nontransformed cells such as 32D, NIH3T3, or human leukocytes. All compounds showed cytotoxic activity on all tested cell lines, accompanied by DNA synthesis inhibition and arrest in the G(0)/G(1) phase. Bobel-16, Bobel-4, and Bobel-24 induced a caspase-independent cell death in K562 and Raji cells, accompanied by chromatin condensation, cytochrome c release, and dissipation of mitochondrial membrane potential in a concentration-dependent manner and production of reactive oxygen species. As the proto-oncogene MYC is involved in mitochondrial biogenesis and survival of leukemia cells, we tested its effect on bobel activity. Bobel-24 induced down-regulation of MYC in K562 and, consistently, ectopic expression of MYC results in partial protection towards the cytotoxic effect of Bobel-24. In conclusion, Bobel derivatives induce a caspase- and Bcl-2-independent cell death in which mitochondrial permeabilization and MYC down-regulation are involved. Bobels may serve as prototypes for the development of new agents for the therapy of leukemia.
Mol Cancer Ther 2006 May
PMID:Novel triiodophenol derivatives induce caspase-independent mitochondrial cell death in leukemia cells inhibited by Myc. 1673 48

We have previously shown that c-MYC-induced mammary tumorigenesis in mice proceeds via a preferred secondary pathway involving spontaneous activating mutations in Kras2 (C. M. D'Cruz, E. J. Gunther, R. B. Boxer, J. L. Hartman, L. Sintasath, S. E. Moody, J. D. Cox, S. I. Ha, G. K. Belka, A. Golant, R. D. Cardiff, and L. A. Chodosh, Nat. Med. 7:235-239, 2001). In contrast, we now demonstrate that Wnt1-induced mammary tumorigenesis proceeds via a pathway that preferentially activates Hras1. In addition, we find that expression of oncogenic forms of Kras2 and Hras1 from their endogenous promoters has markedly different consequences for the progression of tumors to oncogene independence. Spontaneous activating Kras2 mutations occurring in either MYC- or Wnt1-induced tumors were strongly associated with oncogene-independent tumor growth following MYC or Wnt1 downregulation. In contrast, Hras1-mutant Wnt1-induced tumors consistently remained oncogene dependent. Additionally, Kras2-mutant tumors exhibited substantially higher levels of ras-GTP, phospho-Erk1/2, and phospho-Mek1/2 compared to Hras1-mutant tumors, suggesting the involvement of the ras/mitogen-activated protein kinase (MAPK) pathway in the acquisition of oncogene independence. Consistent with this, by use of carcinogen-induced ras mutations as well as knock-in mice harboring a latent activated Kras2 allele, we demonstrate that Kras2 activation strongly synergizes with both c-MYC and Wnt1 in mammary tumorigenesis and promotes the progression of tumors to oncogene independence. Together, our findings support a model for tumorigenesis in which c-MYC and Wnt1 select for the outgrowth of cells harboring mutations in specific ras isoforms and that these secondary mutations, in turn, determine the extent of ras/MAPK pathway activation and the potential for oncogene-independent growth.
Mol Cell Biol 2006 Nov
PMID:Isoform-specific ras activation and oncogene dependence during MYC- and Wnt-induced mammary tumorigenesis. 1690 35

Methionine deprivation stress (MDS) eliminates mitotic activity in melanoma cells regardless of stage, grade, or TP53 status, whereas it has a negligible effect on normal skin fibroblasts. In most cases, apoptosis accounts for the elimination of up to 90% of tumor cells from the culture within 72 hours after MDS, leaving a scattered population of multinucleated resistant cells. Loss of mitosis in tumor cells is associated with marked reduction of cyclin-dependent kinase (CDK) 1 transcription and/or loss of its active form (CDK1-P-Thr(161)), which is coincident with up-regulation of CDKN1A, CDKN1B, and CDKN1C (p21, p27, and p57). Expression of the proapoptotic LITAF, IFNGR, EREG, TNFSF/TNFRSF10 and TNFRSF12, FAS, and RNASEL is primarily up-regulated/induced in cells destined to undergo apoptosis. Loss of Aurora kinase B and BIRC5, which are required for histone H3 phosphorylation, is associated with the accumulation of surviving multinucleated cells. Nevertheless, noncycling survivors of MDS are sensitized to temozolomide, carmustin, and cisplatin to a much greater extent than normal skin fibroblasts possibly because of the suppression of MGMT/TOP1/POLB, MGMT/RAD52/RAD54, and cMET/RADD52, respectively. Sensitivity to these and additional genotoxic agents and radiation may also be acquired due to loss of cMET/OGG1, reduced glutathione reductase levels, and a G(2)-phase block that is a crucial step in the damage response associated with enhancement of drug toxicity. Although the genes controlling mitotic arrest and/or apoptosis in response to low extracellular methionine levels are unknown, it is likely that such control is exerted via the induction/up-regulation of tumor suppressors/growth inhibitor genes, such as TGFB, PTEN, GAS1, EGR3, BTG3, MDA7, and the proteoglycans (LUM, BGN, and DCN), as well as the down-regulation/loss of function of prosurvival genes, such as NFkappaB, MYC, and ERBB2. Although MDS targets several common genes in tumors, mutational variability among melanomas may decide which metabolic and signal transduction pathways will be activated or shutdown.
Mol Cancer Res 2006 Aug
PMID:Mitotic arrest, apoptosis, and sensitization to chemotherapy of melanomas by methionine deprivation stress. 1690 95

Unmethylated CpG motifs interact with Toll-like receptor 9 (TLR9), triggering an innate immune response characterized by the production of cytokines, chemokines and immunoglobulins. Microarray analysis of cDNA from murine spleen cells stimulated with CpG oligodeoxynucleotides (ODN) identified reproducible changes in gene expression over time. Eight genes are significantly up-regulated 2h post CpG ODN stimulation, most of which contribute to the induction of innate or adaptive immune responses. Network analysis indicates that TNF and NFKB1 are key regulators of gene expression at this early time point. At 4h, IL1B in addition to TNF and NFKB1 play dominant roles in the up-regulation of immune gene expression, whereas by 8h this function is mediated by TNF, IFNG, and MYC. Genes responsible for down-regulating CpG-induced responses were also identified, dampening what would otherwise be a continuous positive feedback loop. This work provides novel insights into the regulatory process embedded in the gene expression profile induced by CpG ODN, identifies novel genes associated with CpG-induced immune stimulation, and clarifies the breadth of the immune response elicited via TLR9.
Mol Immunol 2007 Feb
PMID:CpG-mediated changes in gene expression in murine spleen cells identified by microarray analysis. 1693 Jul 9

Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (> 2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (> 2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (> 2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.
Mol Cell Biol 2006 Oct
PMID:Functional analysis of p53 binding under differential stresses. 1698 Jun 8


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