c-myc
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Nuclear locations of the c-myc gene and its transcripts (c-myc (T)) have been investigated in relation to nuclear domains involved in RNA synthesis and processing. Transcription of the c-myc gene appears to be linked to the late G(1)- and preferentially to S-phases of the cell cycle. The c-myc gene and its transcripts were positioned non-randomly within the interphase nucleus; additionally, c-myc RNA signals accumulated at nucleoli. Using oligo-probes, designed to exon II and exon III of the c-myc gene, single c-myc (T) was preferentially observed in human carcinoma HT29 and A549 cells. Conversely, human embryonal teratocarcinoma NTERA cells were characterized by the presence of multiple c-myc RNA signals located in both the nucleoli and nucleoplasm. When accumulated at nucleoli, c-myc (T) occupied the periphery of this organelle, though not those associated with the cultivation surface. In HT29 cells, approximately 80% of c-myc (T) co-localized with the RNAP II positive regions, so-called transcription factories. However, in approximately 20% of the cells with c-myc transcripts, the c-myc (T) was released from the site of synthesis, and was not associated with either transcription factories or SC35 domains. In approximately 60% of nuclei with c-myc (T), these signals were located in close proximity to the SC35 regions, but promyelocytic leukaemia bodies were associated with c-myc (T) only in approximately 20% of the nuclei. Taken together, c-myc RNA signals were positioned in the most internal parts of the cell nuclei preferentially associated with the nucleoli. Specific nuclear and nucleolar positioning probably reflects the kinetics of c-myc RNA metabolism.
- MeSH
- buněčné jádro genetika metabolismus ultrastruktura MeSH
- buňky HT-29 MeSH
- exprese genu MeSH
- financování organizované MeSH
- genetická transkripce MeSH
- geny myc MeSH
- lidé MeSH
- lidské chromozomy, pár 8 MeSH
- messenger RNA metabolismus MeSH
- nádorové buňky kultivované MeSH
- protoonkogenní proteiny c-myc metabolismus MeSH
- RNA-polymerasa II metabolismus MeSH
- tkáňová distribuce MeSH
- Check Tag
- lidé MeSH
- MeSH
- buňky stromatu metabolismus MeSH
- finanční podpora výzkumu jako téma MeSH
- imunohistochemie MeSH
- invazivní růst nádoru MeSH
- karcinom in situ metabolismus MeSH
- keratinocyty metabolismus MeSH
- lidé MeSH
- nádory děložního čípku metabolismus MeSH
- protoonkogenní proteiny c-myc fyziologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
In last few years, numerous groups of proteins participating in the regulation of cell proliferation, differentiation and death during ontogenesis have been described. In this study we compared the occurrence of Bcl-2, p53 and myc protein families with the level of proliferative activity and apoptosis during development of duodenal epithelium. Paraffin embedded tissues of eight human embryos and foetuses aged from the 6th-18th week of IUD were used. For the detection of apoptotic cells the TUNEL method was performed, the proliferative marker PCNA and all the proteins studied were detected by means of indirect three-step immunohistochemical method. In the 6th and 8th week of intrauterine development we observed isolated TUNEL positive epithelial cells only and this was accompanied by the disperse presence of PCNA as well as by all the studied proteins: Bcl-2, Bax, Bcl-XL, c-myc, N-myc, p53, p63 and p73. In the early foetal period of duodenal development we registered changes in PCNA and TUNEL positivity in accordance with the constitution of the stem cell pool on base of villi, where more numerous Bcl-2 positive cells were also found. The separation of primitive crypts and villi was not accompanied by any differences in distribution of Bax, Bcl-XL, c-myc, N-myc, p63 and p73 proteins between those compartments: all the studied proteins showed dispersed character. P53 rapidly decreased in this period. In the 18th week of intrauterine development the balance between proliferation in crypts and apoptosis of villi epithelium was well established and no p53 positive cells were found. In the presence of Bcl-2, Bax, Bcl-XL, p63 and p73 we did not find any dramatic changes. The myc proteins were restricted within the epithelium of the Lieberkuhn crypts only.
- MeSH
- apoptóza MeSH
- duodenum cytologie embryologie metabolismus MeSH
- embryo savčí metabolismus MeSH
- epitel embryologie metabolismus MeSH
- imunohistochemie MeSH
- lidé MeSH
- nádorový supresorový protein p53 analýza MeSH
- proliferace buněk MeSH
- protoonkogenní proteiny c-bcl-2 analýza MeSH
- protoonkogenní proteiny c-myc analýza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The transcription factor c-Myc, a key regulator of cellular processes, has long been associated with roles in cell proliferation and apoptosis. This review analyses the multiple functions of c-Myc by examining the different c-Myc isoforms in detail. The impact of different c-Myc isoforms, in particular p64 and p67, on fundamental biological processes remains controversial. It is necessary to investigate the different isoforms in the context of proto-oncogenesis. The current knowledge base suggests that neoplastic lesions may possess the means for self-destruction via increased c-Myc activity. This review presents the most relevant information on the c-Myc locus and focuses on a number of isoforms, including p64 and p67. This compilation provides a basis for the development of therapeutic approaches that target the potent growth arresting and pro-apoptotic functions of c-Myc. This information can then be used to develop targeted interventions against specific isoforms with the aim of shifting the oncogenic effects of c-Myc from pro-proliferative to pro-apoptotic. The research summarised in this review can deepen our understanding of how c-Myc activity contributes to different cellular responses, which will be crucial in developing effective therapeutic strategies; for example, isoform-specific approaches may allow for precise modulation of c-Myc function.
We have examined the effect of sodium butyrate (SB) on the viability of normal peripheral blood lymphocytes (PBLs) in vitro and the effect of this agent on the expression of 20 apoptosis-related genes. Data suggest that PBL treated with 2 mmol L(-1) SB resisted for at least 8 h the destructive activity of the agent, but eventually 30% of cells died within 72 h. As documented by flow cytometry and cytochrome c release study, cells underwent mitochondrial-derived apoptosis. While the expression of the majority of genes examined by RT-PCR and Western blots remained indifferent to 2 mmol L(-1) SB, the cellular levels of BimEL, c-myc, p53, and p21(WAF1) varied profoundly with the time of SB treatment. The Bax activator BimEL increased rapidly, driving cells toward apoptosis likely controlled by c-myc and p21(WAF1) activities. The c-myc, exercising the role of mediator of the function of BimEL and inhibitor of p21(WAF1) expression, decreased significantly for several hours after adding SB but within 48 h it returned to close to its original value. An apoptosis inhibitor and executive caspase substrate p21(WAF1) increased early at the beginning of treatment but subsequently, within a time frame of 72 h, profoundly dropped in terms of both a caspase-dependent and caspase-independent way. We suggest that variations in c-myc and p21(WAF1) expression delay apoptosis making PBL resistant to SB for several hours, and together with fast catabolism of SB in vivo protect PBL against the destructive activity of this anti-cancerous metabolite of colonic bacteria. (c) 2008 John Wiley & Sons, Ltd.
- MeSH
- aktivace enzymů MeSH
- apoptóza účinky léků MeSH
- cytochromy c metabolismus sekrece MeSH
- financování organizované MeSH
- inhibitor p21 cyklin-dependentní kinasy genetika metabolismus MeSH
- intracelulární membrány účinky léků MeSH
- kaspasy metabolismus MeSH
- kolagen typ XI metabolismus MeSH
- kultivované buňky MeSH
- kyselina máselná farmakologie MeSH
- lidé MeSH
- lymfocyty metabolismus sekrece účinky léků MeSH
- membránové proteiny genetika metabolismus MeSH
- mitochondrie účinky léků MeSH
- proteiny regulující apoptózu genetika metabolismus MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- protoonkogenní proteiny genetika metabolismus MeSH
- reaktivní formy kyslíku metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- Check Tag
- lidé MeSH
The general mechanism underlying the tumor suppressor activity of the Hippo signaling pathway remains unclear. In this study, we explore the molecular mechanisms connecting the Hippo signaling pathway with glucose metabolism. We have found that two key regulators of glycolysis, C-MYC and GLUT1, are targets of the Hippo signaling pathway in human leukemia cells. Our results revealed that activation of MST1 by the natural compound shikonin inhibited the expression of GLUT1 and C-MYC. Furthermore, RNAi experiments confirmed the regulation of GLUT1 and C-MYC expression via the MST1-YAP1-TEAD1 axis. Surprisingly, YAP1 was found to positively regulate C-MYC mRNA levels in complex with TEAD1, while it negatively regulates C-MYC levels in cooperation with MST1. Hence, YAP1 serves as a rheostat for C-MYC, which is regulated by MST1. In addition, depletion of MST1 stimulates lactate production, whereas the specific depletion of TEAD1 has an opposite effect. The inhibition of lactate production and cellular proliferation induced by shikonin also depends on the Hippo pathway activity. Finally, a bioinformatic analysis revealed conserved TEAD-binding motifs in the C-MYC and GLUT1 promoters providing another molecular data supporting our observations. In summary, regulation of glucose metabolism could serve as a new tumor suppressor mechanism orchestrated by the Hippo signaling pathway.
- MeSH
- adaptorové proteiny signální transdukční účinky léků MeSH
- apoptóza účinky léků genetika MeSH
- DNA vazebné proteiny účinky léků MeSH
- fosfoproteiny účinky léků metabolismus MeSH
- geny myc účinky léků MeSH
- hepatocytární růstový faktor MeSH
- jaderné proteiny účinky léků MeSH
- lidé MeSH
- naftochinony farmakologie MeSH
- přenašeč glukosy typ 1 metabolismus MeSH
- proliferace buněk účinky léků genetika MeSH
- protoonkogenní proteiny účinky léků MeSH
- signální transdukce účinky léků fyziologie MeSH
- transkripční faktory účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
