Disease relevance of Myc

• Yet Kras-transformed mouse colonocytes lacking p53 formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth [1].
• However, Myc is also induced in many postmitotic tissues, including adult myocardium, in response to stress where the predominant form of growth is an increase in cell size (hypertrophy) and not number [2].
• We also found that cyclins E1 and E2 are expressed at high levels in mouse breast tumors driven by the Myc oncogene [3].
• Transgenic progeny from one of these lines can be induced to develop T-ALL by injecting Cre RNA into one-cell-stage embryos, demonstrating the utility of the Cre/lox system in the zebrafish and providing an essential step in preparing this model for chemical and genetic screens designed to identify modifiers of Myc-induced T-ALL [4].
• Remarkably, inactivation of even a single allele of Bim accelerated Myc-induced development of tumors, particularly acute B cell leukemia [5].
• Our study demonstrates that 3' IgH enhancers alone can deregulate c-myc and initiate the development of BL-like lymphomas [6].
• We show in a beta-cell tumor model that activation of Myc in vivo triggers rapid recruitment of mast cells to the tumor site-a recruitment that is absolutely required for macroscopic tumor expansion [7].

Psychiatry related information on Myc

• Although approximately one-half of single transgenic c-myc virgin females also eventually developed mammary gland tumors, these were stochastic and arose after a long latency period of 9-12 months [8].
• The effects of c-myc were further dissected by showing that c-myc can inhibit differentiation independently of Id, a negative regulator of muscle differentiation [9].

High impact information on Myc

• These findings establish a role for microRNAs in non-cell-autonomous Myc-induced tumor phenotypes [1].
• Blimp1 appears to govern cellular input into the gland since its loss leads to elevated c-myc expression, augmented cell proliferation, and SG hyperplasia [10].
• Predictions validated in transgenic mouse embryos revealed the presence of multiple tissue-specific enhancers in mouse c-Myc and N-Myc genes, which has implications for organ-specific growth control and tumor-type specificity of oncogenes [11].
• HectH9-mediated ubiquitination of Myc is required for transactivation of multiple target genes, recruitment of the coactivator p300, and induction of cell proliferation by Myc [12].
• Here we show that the E3 ubiquitin ligase HectH9 ubiquitinates Myc in vivo and in vitro, forming a lysine 63-linked polyubiquitin chain [12].

Chemical compound and disease context of Myc

• It thus appears likely that an increase in the ODC mRNA levels and, to a lesser extent, an increase in c-myc mRNA levels may be some of the important mechanisms by which estradiol mediates its growth effects on colon cancer cells in vivo [13].
• Phenobarbital promotes liver growth in c-myc/TGF-alpha transgenic mice by inducing hypertrophy and inhibiting apoptosis [14].
• Small interfering RNA of c-Myc, however, blocked proliferation of SOD2 homozygous (SOD2-/-) astrocytes under mild hypoxia consisting of 5% O2, whereas it did not affect the growth of wild-type astrocytes [15].
• The observations from this study suggest that both FO and vitamin E modulate the levels of specific cytokines, decrease the levels of proinflammatory cytokines, inflammatory lipid mediators, and c-myc, and increase TGF-beta1 levels in spleens of MRL/lpr mice and thus may delay the progress of autoimmune diseases [16].
• The expression of c-myc and c-H-ras in hyperplastic nodules and hepatocellular carcinomas induced in male B6C3F1 mice after chronic administration of dichloroacetate (DCA) and trichloroacetate (TCA) was studied using in situ hybridization [17].

Biological context of Myc

• Numerous experiments have also demonstrated a critical role for both Myc and Ras activities in allowing cell-cycle progression [18].
• Our data suggest that Src kinases control the transcriptional activation of Myc [19].
• This antagonism relates partly to their ability to compete with Myc for the protein Max and for consensus DNA binding sites and to recruit transcriptional co-repressors [20].
• Our results show that Mxi1 is involved in the homeostasis of differentiated organ systems, acts as a tumour suppressor in vivo, and engages the Myc network in a functionally relevant manner [20].
• Here we report that p53 and ARF also potentiate Myc-induced apoptosis in primary pre-B-cell cultures, and that spontaneous inactivation of the ARF-Mdm2-p53 pathway occurs frequently in tumors arising in Emu-myc transgenic mice [21].

Anatomical context of Myc

• Both AP1 and Myc are activated in fibroblasts in response to growth factor stimulation, and various experiments suggest their importance in proliferation [19].
• Deregulated expression of c-myc can induce cell proliferation in established cell lines and in primary mouse embryonic fibroblasts (MEFs), through a combination of both transcriptional activation and repression by Myc [22].
• Myc-deficient hearts demonstrated attenuated stress-induced hypertrophic growth, secondary to a reduction in cell growth of individual myocytes [2].
• Therefore, to explore Myc's role in hypertrophic growth, we created mice where Myc can be inducibly inactivated, specifically in adult myocardium [2].
• Hypertrophic growth in cardiac myocytes is mediated by Myc through a Cyclin D2-dependent pathway [2].

Associations of Myc with chemical compounds

• Further, in isoleucine-deprived cells, Myc induces apoptosis without altering cdk activity [23].
• After induction of Myc, p27 phosphorylated at threonine 187 transiently accumulates in a non cdk2 bound form [24].
• Myc-induced apoptosis operates through ODC and can be prevented with the ODC inhibitor, alpha-difluoromethylornithine (DFMO) [25].
• In contrast, NMDA virtually did not alter DNA binding activities of both CREB and Myc in discrete structures of murine brain under similar experimental conditions [26].
• Induction of c-myc transcription by the v-Abl tyrosine kinase requires Ras, Raf1, and cyclin-dependent kinases [27].

Physical interactions of Myc

• CpG methylation of the recognition site greatly inhibits DNA binding, suggesting that DNA methylation may regulate the c-Myc/Myn complex in vivo [28].
• The c-myc oncogene is commonly amplified in breast cancer and is known to interact synergistically with transforming growth factor alpha (TGF alpha) in vitro to promote phenotypic transformation of mammary epithelial cells [8].
• 125I-EGF binding and Scatchard analysis indicated a single class of high affinity receptors with the total number of binding sites of 1.2 X 10(4) +/- 600 and 2.5 X 10(5) +/- 1000 sites/cell in the normal and c-myc hepatocytes in primary culture, respectively [29].
• Repression via c-Myc occurs at the initiator elements, whereas a c-Myc-interacting protein (Miz-1) stimulates transcription [30].
• Myc family transcription factors are destabilized by phosphorylation of a conserved amino-terminal GSK-3beta motif [31].

Enzymatic interactions of Myc

• In the parental S194 cells, one allele of the c-myc was rearranged and its 5'-flanking region was partially deleted by recombination with the immunoglobulin C alpha gene [32].

Co-localisations of Myc

• Arf and Mdm2 co-localize in the nucleolus in response to activation of the oncoprotein Myc and as mouse fibroblasts undergo replicative senescence [33].

Regulatory relationships of Myc

• The protracted latent period before the onset of frank disease likely reflects the ability of c-Myc to induce a p53-dependent apoptotic program that initially protects animals against tumor formation but is disabled when overtly malignant cells emerge [21].
• Our results also establish a requirement for activated cyclin-dependent kinases (cdks), as v-Abl-dependent induction of c-myc transcription is blocked by cdk inhibitor p21 and induction of c-myc is accompanied by activation of cdk2 and cdk4 [27].
• Ectopic c-Myc expression overrode apoptosis induced by TGF beta 1 [34].
• Since we have demonstrated NF-kappa/Rel factors play a key role in transcriptional control of c-myc, we explored the effects of TGF beta1 on WEHI 231 immature B cells [34].
• B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription [35].
• C-Myc-activated Casp3(-/-) mice were protected from streptozotocin-induced diabetes [36].

Other interactions of Myc

• We suggest that interaction of Myn with c-Myc stabilizes sequence-specific DNA binding in vivo [28].
• In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway [37].
• In contrast, Fos and Jun, but not Myc, rescued the block induced by dominant negative Ras [19].
• Ha-ras and c-myc oncogene expression interferes with morphological and functional differentiation of mammary epithelial cells in single and double transgenic mice [38].
• However, in contrast to other aspects of v-Abl signaling, induction of c-myc transcription is independent of the Rac GTPase [27].

Analytical, diagnostic and therapeutic context of Myc

• In contrast, neither microinjection of cdk inhibitors nor chemical inhibition of cdk2 affected the ability of Myc to induce apoptosis in serum-starved cells [23].
• c-Myc (Myc) is highly expressed in developing embryos where it regulates body size by controlling proliferation but not cell size [2].
• Chromatin immunoprecipitation analysis spanning the entire PRDX3 genomic sequence reveals that Myc binds preferentially to a 930-bp region surrounding exon 1 [39].
• To study its role in AML, we used a murine stem cell virus (MSCV) retroviral gene transfer/transplantation system to broadly express Myc in the bone marrow of mice either alone or in combination with antiapoptotic mutations [40].
• Omomyc sequestered Myc in complexes with low DNA binding efficiency, preventing binding to Max and inhibiting Myc transcriptional activator function [41].

References