Klíčové buněčné procesy včetně proliferace, diferenciace a přežívání jsou často regulovány stejnými molekulami během ontogeneze a tumorigeneze. Je známo, že protein c-Myb se spolupodílí na řízení uvedených procesů. Aberantní aktivace tohoto proteinu narušuje rovnováhu v jejich regulaci a podporuje zvýšenou proliferaci a přežívání buněk, čímž přispívá k maligní transformaci. Náš předchozí výzkum ukázal, že c-Myb se podílí také na regulaci fyziologického vývoje kostí. Nedávno publikované výsledky, podpořené našimi preliminárními daty, potvrdily, že protein c-Myb je exprimován v osteosarkomech, nádorech kostní tkáně, které se vyznačují věkově specifickou incidencí. Cílem tohoto projektu je objasnění funkce proteinu c-Myb v různých fázích fyziologického vývoje kostí a především jeho významu v regulaci progrese a chemorezistence osteosarkomů. s využitím buněčných linií, in vivo modelů a klinické studie. Klinická část bude dále rozšířena o širší spektrum osteogenních patologií s typickým výskytem v období dospívání, což přispěje ke zhodnocení významu proteinu c-Myb v homeostáze kostí.; Ontogenesis and tumorigenesis often share regulatory molecules that modulate key cellular events including cell proliferation, differentiation and survival. The c-Myb protein has been associated with control of these processes. Aberrant activation of c-Myb disturbs the balance in favor of proliferation and survival, thus contributing to malignant transformation. Our earlier research showed that c-Myb is involved in regulation of embryonal bone development. Recent findings, including preliminary data presented by us, demonstrate that c-Myb is expressed in osteosarcomas, bone tumors with specific age-related incidence. The aim of this study is to clarify the function of c-Myb in different stages of physiological bone development, and most importantly, the relevance of c-Myb in control of osteosarcoma progression and chemoresistance using cell lines, in vivo models and a clinical study. The clinical part will be further extended to other osteogenic pathologies with high incidence in childhood to further assess the importance of c-Myb in bone homeostasis in humans.

• MeSH
• chemorezistence MeSH
• geny myb MeSH
• homeostáza MeSH
• karcinogeneze genetika   MeSH
• mladiství MeSH
• osteogeneze genetika   MeSH
• osteosarkom farmakoterapie   genetika   MeSH
• Check Tag
• mladiství MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• onkologie
• genetika, lékařská genetika
• osteologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

The c-myb proto-oncogene and its oncogenic derivative v-mybAMV encode transcriptional regulators engaged in the commitment of hematopoietic cells. While the c-Myb protein is important for the formation and differentiation of various progenitors, the v-MybAMV oncoprotein induces in chicks a progression and transformation of the single (monoblastic) cell lineage. Here we present the first evidence of cell fate-directing abilities of c-Myb and v-MybAMV proteins in avian neural crest (NC), where both proteins determine melanocytogenesis. The increased concentration of c-Myb induces progression into dendritic melanocytes and differentiation. The v-myb oncogene converts essentially all NC cells into melanocytes and causes their transformation. Both Myb proteins activate in NC cells expression of the c-kit gene and stem cell factor c-Kit signaling--one of the essential pathways in melanocyte development. These observations suggest that the c-myb-c-kit pathway represents a common regulatory scheme for both hematopoietic and neural progenitors and establishes a novel experimental model for studies of melanocytogenesis and melanocyte transformation.

• MeSH
• buněčná diferenciace MeSH
• crista neuralis cytologie   metabolismus   MeSH
• DNA primery genetika   MeSH
• financování organizované MeSH
• geny myb MeSH
• kuřecí embryo MeSH
• melanocyty cytologie   metabolismus   MeSH
• onkogenní proteiny v-myb genetika   metabolismus   MeSH
• protoonkogenní proteiny c-kit genetika   metabolismus   MeSH
• protoonkogenní proteiny c-myb genetika   metabolismus   MeSH
• růstový faktor kmenových buněk genetika   metabolismus   MeSH
• sekvence nukleotidů MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• zvířata MeSH

The Myb locus encodes the c-Myb transcription factor involved in controlling a broad variety of cellular processes. Recently, it has been shown that c-Myb may play a specific role in hard tissue formation; however, all of these results were gathered from an analysis of intramembranous ossification. To investigate a possible role of c-Myb in endochondral ossification, we carried out our study on the long bones of mouse limbs during embryonic development. Firstly, the c-myb expression pattern was analyzed by in situ hybridization during endochondral ossification of long bones. c-myb positive areas were found in proliferating as well as hypertrophic zones of the growth plate. At early embryonic stages, localized expression was also observed in the perichondrium and interdigital areas. The c-Myb protein was found in proliferating chondrocytes and in the perichondrium of the forelimb bones (E14.5-E17.5). Furthermore, protein was detected in pre-hypertrophic as well as hypertrophic chondrocytes. Gain-of-function and loss-of-function approaches were used to test the effect of altered c-myb expression on chondrogenesis in micromass cultures established from forelimb buds of mouse embryos. A loss-of-function approach using c-myb specific siRNA decreased nodule formation, as well as downregulated the level of Sox9 expression, a major marker of chondrogenesis. Transient c-myb overexpression markedly increased the formation of cartilage nodules and the production of extracellular matrix as detected by intense staining with Alcian blue. Moreover, the expression of early chondrogenic genes such as Sox9, Col2a1 and activity of a Col2-LUC reporter were increased in the cells overexpressing c-myb while late chondrogenic markers such as Col10a1 and Mmp13 were not significantly changed or were downregulated. Taken together, the results of this study demonstrate that the c-Myb transcription factor is involved in the regulation and promotion of endochondral bone formation.

• MeSH
• biologické markery metabolismus   MeSH
• buněčná diferenciace MeSH
• chondrogeneze fyziologie   MeSH
• hybridizace in situ MeSH
• končetiny embryologie   MeSH
• myši MeSH
• protoonkogenní proteiny c-myb genetika   fyziologie   MeSH
• umlčování genů MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• buněčné jadérko metabolismus   MeSH
• buněčné struktury metabolismus   MeSH
• geny myb genetika   MeSH
• onkogenní proteiny v-myb metabolismus   MeSH
• protoonkogenní proteiny c-myb metabolismus   MeSH
• Spodoptera MeSH

• MeSH
• fosforylace MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• protoonkogenní proteiny c-myb chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH

The MYB gene codes for the c-Myb transcription factor maintaining proliferation of colon epithelial progenitors, thus controlling colon development and homeostasis. This gene is overexpressed in early phases of colorectal cancer (CRC) tumorigenesis. The aim of this study was to examine the expression of c-Myb in CRC tissue samples both at the messenger RNA (mRNA) and protein levels and to evaluate their associations with clinicopathological characteristics in a group of 108 CRC patients. Statistically significant negative association was found between the frequency of the c-Myb-positive tumor cells assessed by immunohistochemistry and the presence of distant metastases (p < 0.01) but not tumor differentiation, tumor stage, lymph node involvement, vascular invasion, tumor localization, age, and gender of the patients. Although the c-Myb protein level in the tumor tissue correlated with its mRNA level, no significant association between MYB mRNA and any clinicopathological characteristics was observed. We conclude that albeit overexpression of c-Myb is considered as an important factor contributing to early phases of CRC tumorigenesis, it may later have negative effect on tumor cell dissemination as observed recently in breast cancer as well. Further studies are required to explain the role of c-Myb during formation of CRC distant metastases.

• MeSH
• adenokarcinom genetika   sekundární   MeSH
• buněčná diferenciace MeSH
• dospělí MeSH
• down regulace MeSH
• geny myb * MeSH
• invazivní růst nádoru MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• messenger RNA biosyntéza   MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• protoonkogenní proteiny c-myb biosyntéza   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• RNA nádorová biosyntéza   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Satellite cells represent a heterogeneous population of stem and progenitor cells responsible for muscle growth, repair and regeneration. We investigated whether c-Myb could play a role in satellite cell biology because our previous results using satellite cell-derived mouse myoblast cell line C2C12 showed that c-Myb was expressed in growing cells and downregulated during differentiation. We detected c-Myb expression in activated satellite cells of regenerating muscle. c-Myb was also discovered in activated satellite cells associated with isolated viable myofiber and in descendants of activated satellite cells, proliferating myoblasts. However, no c-Myb expression was detected in multinucleated myotubes originated from fusing myoblasts. The constitutive expression of c-Myb lacking the 3' untranslated region (3' UTR) strongly inhibited the ability of myoblasts to fuse. The inhibition was dependent on intact c-Myb transactivation domain as myoblasts expressing mutated c-Myb in transactivation domain were able to fuse. The absence of 3' UTR of c-Myb was also important because the expression of c-Myb coding region with its 3' UTR did not inhibit myoblast fusion. The same results were repeated in C2C12 cells as well. Moreover, it was documented that 3' UTR of c-Myb was responsible for downregulation of c-Myb protein levels in differentiating C2C12 cells. DNA microarray analysis of C2C12 cells revealed that the expression of several muscle-specific genes was downregulated during differentiation of c-Myb-expressing cells, namely: ACTN2, MYH8, TNNC2, MYOG, CKM and LRRN1. A detailed qRT-PCR analysis of MYOG, TNNC2 and LRRN1 is presented. Our findings thus indicate that c-Myb is involved in regulating the differentiation program of myogenic progenitor cells as its expression blocks myoblast fusion.

• MeSH
• 3' nepřekládaná oblast genetika   MeSH
• buněčná diferenciace genetika   MeSH
• buněčné linie MeSH
• fúze buněk MeSH
• imunohistochemie MeSH
• kardiotoxiny farmakologie   MeSH
• kosterní svalová vlákna cytologie   metabolismus   MeSH
• kosterní svaly účinky léků   patofyziologie   MeSH
• kultivované buňky MeSH
• myoblasty cytologie   metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• protoonkogenní proteiny c-myb genetika   metabolismus   MeSH
• regenerace účinky léků   genetika   MeSH
• satelitní buňky kosterního svalu cytologie   metabolismus   MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• stanovení celkové genové exprese MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Rhabdomyosarcomas (RMS) are a heterogeneous group of mesodermal tumors, the most common sub-types are embryonal (eRMS) and alveolar (aRMS) rhabdomyosarcoma. Immunohistochemical analysis revealed c-Myb expression in both eRMS and aRMS. c-Myb has been reported to be often associated with malignant human cancers. We therefore investigated the c-Myb role in RMS using cellular models of RMS. Specific suppression of c-Myb by a lentiviral vector expressing doxycycline (Dox)-inducible c-Myb shRNA inhibited proliferation, colony formation, and migration of the eRMS cell line (RD), but not of the aRMS cell line (RH30). Upon c-Myb knockdown in eRMS cells, cells accumulated in G0/G1 phase, the invasive behaviour of cells was repressed, and elevated levels of myosin heavy chain, marker of muscle differentiation, was detected. Next, we used an RD-based xenograft model to investigate the role of c-Myb in eRMS tumorigenesis in vivo. We found that Dox administration did not result in efficient suppression of c-Myb in growing tumors. However, when c-Myb-deficient RD cells were implanted into SCID mice, we observed inefficient tumor grafting and attenuation of tumor growth during the initial stages of tumor expansion. The presented study suggests that c-Myb could be a therapeutic target in embryonal rhabdomyosarcoma assuming that its expression is ablated.

• MeSH
• embryonální rhabdomyosarkom genetika   metabolismus   patologie   MeSH
• G0 fáze * MeSH
• G1 fáze * MeSH
• genový knockdown MeSH
• karcinogeneze genetika   metabolismus   patologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protoonkogenní proteiny c-myb genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

c-Myb, known to play a central role in hematopoiesis, is also an important factor involved in myogenesis. Here, we found that the c-myb gene is expressed in proliferating C2C12 myoblasts and turned off in differentiating cells. Detailed analysis of c-myb RNAs revealed that the cell density is the essential factor determining c-myb expression. Both c-myb and its alternatively spliced form c-mybE9A RNAs are down-regulated in confluent cells. Constitutive expression of exogenous c-myb in C2C12 cells inhibits their terminal differentiation. It is shown that the c-Myb protein physically interacts with MyoD, the key regulator of myogenesis, and inhibits MyoD-dependent transcription. The interaction domains are the DNA binding domain of c-Myb and the bHLH motif of MyoD. Our data suggest that in proliferating cells c-Myb binds MyoD and inhibits its transcriptional activity until cell-cell contacts are established and c-myb expression is switched off. Thus, the c-Myb protein may be one of factors ensuring that proliferating myoblasts remain undifferentiated.

• MeSH
• buněčná diferenciace fyziologie   MeSH
• buněčné linie MeSH
• financování organizované MeSH
• myoblasty cytologie   metabolismus   MeSH
• MyoD Protein antagonisté a inhibitory   metabolismus   MeSH
• myogenní regulační faktory biosyntéza   MeSH
• myši inbrední C3H MeSH
• myši MeSH
• počet buněk MeSH
• promotorové oblasti (genetika) MeSH
• protoonkogenní proteiny c-myb biosyntéza   fyziologie   genetika   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

Adenoidně cystický karcinom je druhým až třetím nejčastějším maligním neoplazmatem velkých a převládající nádorovou jednotkou tumorů malých slinných žláz. Podobně jako některé další nádory této onkologické skupiny jej charakterizuje obtížná předpověď klinického průběhu. To je důvodem pro intenzivní hledání nových prognostických a prediktivních molekulárně biologických markerů. Jde především o identifikaci genů, resp. jejich produktů, odpovědných za iniciaci, progresi a metastázování nádorů. Kromě toho se přepokládá, že jejich cílenou biologickou blokádou by bylo možno zlepšit křivky přežití u prognosticky závažných salivárních nádorů vysokého stupně malignity. Práce podává přehled poznatků o dvou v posledních letech intenzivně zkoumaných genetických alterací, týkajících se C-kit a MYB genu a jejich významu pro diagnostiku, prognózu a cílenou terapii adenoidně cystického karcinomu slinných žláz.

Adenoid cystic carcinoma is the second to third most common malignant tumor of major and predominant neoplasm of minor salivary glands. Along with some other salivary carcinomas, ACC is characterized with difficulties in the prediction of its clinical course. Consequently, new prognostic and predictive molecular biomarkers are being sought. This mainly concerns the identification of genes and related products, responsible for the initiation, progression and metastasizings of tumors. Furthermore, it is supposed that the targeted biological blockade could improve survival curves of high grade salivary tumors associated with dismal prognosis. This paper reviews the role of C-kit and MYB genes, in recent years intensively studied genetic alterations in diagnosis, prognosis and targeted treatment of adenoid cystic carcinoma of salivary glands.

• MeSH
• adenoidně cystický karcinom diagnóza   genetika   MeSH
• exprese genu MeSH
• geny myb * genetika   MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• nádory slinných žláz * diagnóza   genetika   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-kit * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH