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
- Cell Nucleus genetics metabolism ultrastructure MeSH
- HT29 Cells MeSH
- Gene Expression MeSH
- Financing, Organized MeSH
- Transcription, Genetic MeSH
- Genes, myc MeSH
- Humans MeSH
- Chromosomes, Human, Pair 8 MeSH
- RNA, Messenger metabolism MeSH
- Tumor Cells, Cultured MeSH
- Proto-Oncogene Proteins c-myc metabolism MeSH
- RNA Polymerase II metabolism MeSH
- Tissue Distribution MeSH
- Check Tag
- Humans 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
- Adaptor Proteins, Signal Transducing drug effects MeSH
- Apoptosis drug effects genetics MeSH
- DNA-Binding Proteins drug effects MeSH
- Phosphoproteins drug effects metabolism MeSH
- Genes, myc drug effects MeSH
- Hepatocyte Growth Factor MeSH
- Nuclear Proteins drug effects MeSH
- Humans MeSH
- Naphthoquinones pharmacology MeSH
- Glucose Transporter Type 1 metabolism MeSH
- Cell Proliferation drug effects genetics MeSH
- Proto-Oncogene Proteins drug effects MeSH
- Signal Transduction drug effects physiology MeSH
- Transcription Factors drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Photodynamic therapy (PDT) is based on the tumor-selective accumulation of photosensitizer followed by irradiation with light of an appropriate wavelength. After irradiation and in the presence of oxygen, photosensitizer induces cellular damage. The aim of this study was to evaluate effects of two photosensitizers TMPyP and ClAlPcS2 on cell lines to obtain better insight into their mechanisms of action. We determined cell viability, reactive oxygen species (ROS) generation and changes in expression levels of two important early response genes, C-MYC and C-FOS, on tumor MCF7 (human breast adenocarcinoma) and G361 (human melanoma) cell lines and non-tumor BJ cell line (human fibroblast) after photodynamic reaction with TMPyP and ClAlPcS2 as photosensitizers. In addition TMPyP and ClAlPcS2 cellular uptake and clearance and antioxidant capacity of the mentioned cell lines were investigated. We found appropriate therapeutic doses and confirmed that both tested photosensitizers are photodynamically efficient in treatment used cells in vitro. TMPyP is more efficient; it had higher ROS production and toxicity after irradiation by intermediate therapeutic doses than ClAlPcS2. We revealed that both TMPyP and ClAlPcS2-PDT increased C-FOS expression on tumor cell lines (G361 and MCF7), but not on non-tumor BJ cell line. Conversely, both TMPyP and ClAlPcS2-PDT decreased C-MYC expression on non-tumor BJ cell line but not on tumor cell lines. As first we tested these photosensitizers in such extent and we believe that it can help to better understand mechanisms of PDT and increase its efficiency and applicability.
- MeSH
- Antioxidants metabolism MeSH
- Photochemotherapy MeSH
- Photosensitizing Agents chemistry therapeutic use toxicity MeSH
- Indoles chemistry therapeutic use toxicity MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Cell Line, Tumor MeSH
- Neoplasms drug therapy MeSH
- Organometallic Compounds chemistry therapeutic use toxicity MeSH
- Porphyrins chemistry therapeutic use toxicity MeSH
- Proto-Oncogene Proteins c-fos metabolism MeSH
- Proto-Oncogene Proteins c-myc metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Light MeSH
- Up-Regulation drug effects radiation effects MeSH
- Cell Survival drug effects radiation effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Cyclin D1 diagnostic use genetics MeSH
- Adult MeSH
- Genes, myc genetics MeSH
- Humans MeSH
- Antibodies, Monoclonal therapeutic use MeSH
- Breast Neoplasms drug therapy secondary therapy MeSH
- Prognosis MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Meeting Abstract 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.
BACKGROUND: Every year about one million women worldwide are diagnosed with breast cancer which is the most common malignancy in female. Of these, triple negative breast carcinoma represents 10-17 %. Triple negative breast carcinomas, characterized by estrogen, progesterone and HER2 receptor negativity are very aggressive tumours with poor prognosis. Individualized treatment (tailored therapy) based on molecular biology markers of tumor and patient is the trend in clinical practice these days. However, molecular targets and predictors for the treatment of triple negative breast carcinoma do not currently exist. METHODS AND RESULTS: This minireview focuses on biomarkers (HER1/EGFR, TOP2A and C-MYC genes) that may predict the response of triple negative breast carcinoma patients to chemotherapy and/or targeted biological treatment with a summary of current knowledge about them. CONCLUSION: HER1 belonging to the HER family of receptors plays an important role in cell proliferation, migration and protection against apoptosis. HER1 protein could be targeted by monoclonal antibodies and/or tyrosine kinase inhibitors (TKIs). Given signal pathway complexity and HER family member cooperation, it may be better to simultaneously target a number of these receptors (e.g. HER1/HER2 by lapatinib). Thus, HER1 assessment could reveal a particular breast cancer patient group with probably good response to HER1 targeted therapy. TOP2A gene, encoding topoisomerase II alpha (target for anthracyclines) is predictive of response to anthracycline therapy. TOP2A aberrations (amplification, deletion) are found in up to approximately 30-90 % of HER2 amplified breast cancer and amplifications are more common than deletions. Recent publications describe TOP2A amplification also in 2.7-8.8 % HER2 nonamplified breast cancers. Patients with a pathologic complete response to anthracycline based neoadjuvant chemotherapy had a good overall prognosis regardless of molecular subtype of breast cancer. These results suggest that particularly tumors with a complete pathological response to anthracyclines could have TOP2A amplification. C-MYC encodes nuclear DNA binding proteins that regulate proliferation and apoptosis; amplification is associated with poor prognosis and hormonally negative breast carcinoma.
- MeSH
- Antigens, Neoplasm analysis genetics MeSH
- Drug Resistance, Neoplasm MeSH
- DNA-Binding Proteins analysis genetics MeSH
- DNA Topoisomerases, Type II analysis genetics MeSH
- ErbB Receptors analysis genetics MeSH
- Financing, Organized MeSH
- Genes, myc genetics MeSH
- Humans MeSH
- Breast Neoplasms drug therapy genetics chemistry MeSH
- Organotechnetium Compounds MeSH
- Oximes MeSH
- Receptor, ErbB-2 analysis MeSH
- Receptors, Estrogen analysis MeSH
- Receptors, Progesterone MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Review 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
- Apoptosis MeSH
- Duodenum cytology embryology metabolism MeSH
- Embryo, Mammalian metabolism MeSH
- Epithelium embryology metabolism MeSH
- Immunohistochemistry MeSH
- Humans MeSH
- Tumor Suppressor Protein p53 analysis MeSH
- Cell Proliferation MeSH
- Proto-Oncogene Proteins c-bcl-2 analysis MeSH
- Proto-Oncogene Proteins c-myc analysis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Stromal Cells metabolism MeSH
- Research Support as Topic MeSH
- Immunohistochemistry MeSH
- Neoplasm Invasiveness MeSH
- Carcinoma in Situ metabolism MeSH
- Keratinocytes metabolism MeSH
- Humans MeSH
- Uterine Cervical Neoplasms metabolism MeSH
- Proto-Oncogene Proteins c-myc physiology MeSH
- Check Tag
- Humans MeSH
- Female MeSH
