The p53 and Mouse double minute 2 (MDM2) proteins are hubs in extensive networks of interactions with multiple partners and functions. Intrinsically disordered regions help to adopt function-specific structural conformations in response to ligand binding and post-translational modifications. Different techniques have been used to dissect interactions of the p53-MDM2 pathway, in vitro, in vivo, and in situ each having its own advantages and disadvantages. This review uses the p53-MDM2 to show how different techniques can be employed, illustrating how a combination of in vitro and in vivo techniques is highly recommended to study the spatio-temporal location and dynamics of interactions, and to address their regulation mechanisms and functions. By using well-established techniques in combination with more recent advances, it is possible to rapidly decipher complex mechanisms, such as the p53 regulatory pathway, and to demonstrate how protein and nucleotide ligands in combination with post-translational modifications, result in inter-allosteric and intra-allosteric interactions that govern the activity of the protein complexes and their specific roles in oncogenesis. This promotes elegant therapeutic strategies that exploit protein dynamics to target specific interactions.

• Klíčová slova
• ATM *, DNA damage response *, MDM2 *, MDMX *, p53 *, p53 mRNA *, post-translational modification *, protein-RNA interactions *, protein-protein interactions *,
• MeSH
• fosforylace genetika   MeSH
• jaderné proteiny MeSH
• lidé MeSH
• myši MeSH
• nádorový supresorový protein p53 genetika   MeSH
• poškození DNA genetika   MeSH
• posttranslační úpravy proteinů genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• protoonkogenní proteiny c-mdm2 genetika   MeSH
• vazba proteinů genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• jaderné proteiny MeSH
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny c-mdm2 MeSH

Activation of p53 by small molecule MDM2 inhibitors can induce cell cycle arrest or death in p53 wildtype cancer cells. However, cancer cells exposed to hypoxia can develop resistance to other small molecules, such as chemotherapies, that activate p53. Here, we evaluated whether hypoxia could render cancer cells insensitive to two MDM2 inhibitors with different potencies, nutlin-3a and navtemadlin. Inhibitor efficacy and potency were evaluated under short-term hypoxic conditions in human and mouse cancer cells expressing different p53 genotypes (wild-type, mutant, or null). Treatment of wild-type p53 cancer cells with MDM2 inhibitors reduced cell growth by > 75% in hypoxia through activation of the p53-p21 signaling pathway; no inhibitor-induced growth reduction was observed in hypoxic mutant or null p53 cells except at very high concentrations. The concentration of inhibitors needed to induce the maximal p53 response was not significantly different in hypoxia compared to normoxia. However, inhibitor efficacy varied by species and by cell line, with stronger effects at lower concentrations observed in human cell lines than in mouse cell lines grown as 2D and 3D cultures. Together, these results indicate that MDM2 inhibitors retain efficacy in hypoxia, suggesting they could be useful for targeting acutely hypoxic cancer cells.

• MeSH
• apoptóza MeSH
• hypoxie genetika   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory * farmakoterapie   genetika   MeSH
• protinádorové látky * farmakologie   MeSH
• protoonkogenní proteiny c-mdm2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• nutlin 3 MeSH Prohlížeč
• protinádorové látky * MeSH
• protoonkogenní proteiny c-mdm2 MeSH

Mouse double minute 2 (MDM2) has a phosphorylation site within a lid motif at Ser17 whose phosphomimetic mutation to Asp17 stimulates MDM2-mediated polyubiquitination of p53. MDM2 lid deletion, but not Asp17 mutation, induced a blue shift in the λ(max) of intrinsic fluorescence derived from residues in the central domain including Trp235, Trp303, Trp323, and Trp329. This indicates that the Asp17 mutation does not alter the conformation of MDM2 surrounding the tryptophan residues. In addition, Phe235 mutation enhanced MDM2 binding to p53 but did not stimulate its ubiquitination function, thus uncoupling increases in p53 binding from its E3 ubiquitin ligase function. However, the Asp17 mutation in MDM2 stimulated its discharge of the UBCH5a-ubiquitin thioester adduct (UBCH5a is a ubiquitin-conjugating enzyme E2D 1 UBC4/5 homolog yeast). This stimulation of ubiquitin discharge from E2 was independent of the p53 substrate. There are now four known effects of the Asp17 mutation on MDM2: (i) it alters the conformation of the isolated N-terminus as defined by NMR; (ii) it induces increased thermostability of the isolated N-terminal domain; (iii) it stimulates the allosteric interaction of MDM2 with the DNA-binding domain of p53; and (iv) it stimulates a novel protein-protein interaction with the E2-ubiquitin complex in the absence of substrate p53 that, in turn, increases hydrolysis of the E2-ubiquitin thioester bond. These data also suggest a new strategy to disrupt MDM2 function by targeting the E2-ubiquitin discharge reaction.

• Klíčová slova
• MDM2, RING domain, allostery, linear motifs, ubiquitination,
• MeSH
• alosterická regulace MeSH
• aminokyselinové motivy MeSH
• bodová mutace * MeSH
• hydrolýza MeSH
• konformace proteinů MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 chemie   metabolismus   MeSH
• polyubikvitin metabolismus   MeSH
• protoonkogenní proteiny c-mdm2 chemie   genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• terciární struktura proteinů MeSH
• ubikvitin konjugující enzymy metabolismus   MeSH
• ubikvitin metabolismus   MeSH
• ubikvitinace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH
• polyubikvitin MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• UBE2D1 protein, human MeSH Prohlížeč
• ubikvitin konjugující enzymy MeSH
• ubikvitin MeSH

Plasticity of cancer cells, manifested by transitions between epithelial and mesenchymal phenotypes, represents a challenging issue in the treatment of neoplasias. Both epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are implicated in the processes of metastasis formation and acquisition of stem cell-like properties. Mouse double minute (MDM) 2 and MDMX are important players in cancer progression, as they act as regulators of p53, but their function in EMT and metastasis may be contradictory. Here, we show that the EMT phenotype in multiple cellular models and in clinical prostate and breast cancer samples is associated with a decrease in MDM2 and increase in MDMX expression. Modulation of EMT-accompanying changes in MDM2 expression in benign and transformed prostate epithelial cells influences their migration capacity and sensitivity to docetaxel. Analysis of putative mechanisms of MDM2 expression control demonstrates that in the context of defective p53 function, MDM2 expression is regulated by EMT-inducing transcription factors Slug and Twist. These results provide an alternative context-specific role of MDM2 in EMT, cell migration, metastasis, and therapy resistance.

• Klíčová slova
• MDM2/MDMX, SNAI2/SLUG, TWIST, epithelial-mesenchymal transition, prostate/breast cancer,
• MeSH
• epitelo-mezenchymální tranzice fyziologie   MeSH
• fenotyp MeSH
• heterografty MeSH
• jaderné proteiny biosyntéza   MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• nádory prsu genetika   metabolismus   patologie   MeSH
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny c-mdm2 biosyntéza   MeSH
• protoonkogenní proteiny biosyntéza   MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• jaderné proteiny MeSH
• MDM2 protein, human MeSH Prohlížeč
• MDM4 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• protoonkogenní proteiny MeSH

OBJECTIVES: Cyclooxygenase-2 (COX-2) and p53 represent molecules linked to oncogenesis of pancreatic cancer, and there is also a known regulatory loop between mouse double minute 2 (MDM2) and p53. The complex cross talks between p53 and COX-2 and scenarios explaining patterns of p53 and COX-2 expressions in precursor and cancer lesions have been recently reported. METHODS: The expressions of COX-2, p53, and MDM2 were examined using immunohistochemistry in 85 resection specimens of pancreatic ductal adenocarcinoma. RESULTS: The positive tumor expression rates of COX-2, p53, and MDM2 were 69.4%, 60.0%, and 41.2%, respectively. Significant correlations between COX-2 and p53 expressions and between p53 and MDM2 expressions were revealed. In the Kaplan-Meier analysis, no statistically significant correlations were found among the levels of COX-2, p53, and MDM2 expressions and survival rates. In the multivariate Cox proportional hazards regression model, grade and nodal status showed to be a valuable predictor of a worse overall survival. CONCLUSIONS: The reported findings confirmed the relationship of p53, MDM2, and COX-2 with the biological process of pancreatic cancer. The expression of none of the examined proteins showed to be a valuable independent prognostic factor. On the contrary, grade and nodal status showed to be a valuable predictor of a worse survival.

• MeSH
• cyklooxygenasa 2 biosyntéza   MeSH
• dospělí MeSH
• duktální karcinom slinivky břišní metabolismus   patologie   chirurgie   MeSH
• imunohistochemie statistika a číselné údaje   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorový supresorový protein p53 biosyntéza   MeSH
• nádory slinivky břišní metabolismus   patologie   chirurgie   MeSH
• pankreatektomie MeSH
• proporcionální rizikové modely MeSH
• protoonkogenní proteiny c-mdm2 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
• práce podpořená grantem MeSH
• Názvy látek
• cyklooxygenasa 2 MeSH
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny c-mdm2 MeSH

The human homologues of murine double minute 2 (MDM2) and 4 (MDM4) negatively regulate p53 tumour suppressor activity and are reported to be frequently overexpressed in human malignancies, prompting clinical trials with drugs that prevent interactions between MDM2/MDM4 and p53. Bone marrow samples from 111 patients with acute myeloblastic leukaemia, myelodysplastic syndrome or chronic myelomonocytic leukaemia were examined for protein (fluorescence-activated cell sorting) and messenger RNA (mRNA) expression (quantitative polymerase chain reaction) of MDM2, MDM4 and tumour protein p53 (TP53). Low protein expression of MDM2 and MDM4 was observed in immature cells from patients with excess of marrow blasts (>5%) compared with CD34+ /CD45low cells from healthy donors and patients without excess of marrow blasts (<5%). The mRNA levels were indistinguishable in all samples examined regardless of disease status or blast levels. Low MDM2 and MDM4 protein expression were correlated with poor survival. These data show a poor correlation between mRNA and protein expression levels, suggesting that quantitative flow cytometry analysis of protein expression levels should be used to predict and validate the efficacy of MDM2 and MDM4 inhibitors. These findings show that advanced disease is associated with reduced MDM2 and MDM4 protein expression and indicate that the utility of MDM2 and MDM4 inhibitors may have to be reconsidered in the treatment of advanced myeloid malignancies.

• Klíčová slova
• acute myeloid leukaemia, murine double minute 2 (MDM2), murine double minute 4 (MDM4), myelodysplastic syndrome, p53,
• MeSH
• akutní myeloidní leukemie * genetika   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• myelodysplastické syndromy * genetika   MeSH
• myši MeSH
• nádorový supresorový protein p53 genetika   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• protoonkogenní proteiny c-mdm2 genetika   metabolismus   MeSH
• protoonkogenní proteiny genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• MDM4 protein, human MeSH Prohlížeč
• messenger RNA MeSH
• nádorový supresorový protein p53 MeSH
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• protoonkogenní proteiny MeSH

MDMX and MDM2 are two nonredundant essential regulators of p53 tumor suppressor activity. MDM2 controls p53 expression levels, whereas MDMX is predominantly a negative regulator of p53 trans-activity. The feedback loops between MDM2 and p53 are well studied and involve both negative and positive regulation on transcriptional, translational and post-translational levels but little is known on the regulatory pathways between p53 and MDMX. Here we show that overexpression of p53 suppresses mdmx mRNA translation in vitro and in cell-based assays. The core domain of p53 binds the 5' untranslated region (UTR) of the mdmx mRNA in a zinc-dependent manner that together with a trans-suppression domain located in p53 N-terminus controls MDMX synthesis. This interaction can be visualized in the nuclear and cytoplasmic compartment. Fusion of the mdmx 5'UTR to the ovalbumin open reading frame leads to suppression of ovalbumin synthesis. Interestingly, the transcription inactive p53 mutant R273H has a different RNA-binding profile compared with the wild-type p53 and differentiates the synthesis of MDMX isoforms. This study describes p53 as a trans-suppressor of the mdmx mRNA and adds a further level to the intricate feedback system that exist between p53 and its key regulatory factors and emphasizes the important role of mRNA translation control in regulating protein expression in the p53 pathway.

• MeSH
• jaderné proteiny metabolismus   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• myši MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protoonkogenní proteiny c-mdm2 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• jaderné proteiny MeSH
• messenger RNA MeSH
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny c-mdm2 MeSH

The identification of the essential role of cyclin-dependent kinases (CDKs) in the control of cell division has prompted the development of small-molecule CDK inhibitors as anticancer drugs. For many of these compounds, the precise mechanism of action in individual tumor types remains unclear as they simultaneously target different classes of CDKs - enzymes controlling the cell cycle progression as well as CDKs involved in the regulation of transcription. CDK inhibitors are also capable of activating p53 tumor suppressor in tumor cells retaining wild-type p53 gene by modulating MDM2 levels and activity. In the current study, we link, for the first time, CDK activity to the overexpression of the MDM4 (MDMX) oncogene in cancer cells. Small-molecule drugs targeting the CDK9 kinase, dinaciclib, flavopiridol, roscovitine, AT-7519, SNS-032, and DRB, diminished MDM4 levels and activated p53 in A375 melanoma and MCF7 breast carcinoma cells with only a limited effect on MDM2. These results suggest that MDM4, rather than MDM2, could be the primary transcriptional target of pharmacological CDK inhibitors in the p53 pathway. CDK9 inhibitor atuveciclib downregulated MDM4 and enhanced p53 activity induced by nutlin-3a, an inhibitor of p53-MDM2 interaction, and synergized with nutlin-3a in killing A375 melanoma cells. Furthermore, we found that human pluripotent stem cell lines express significant levels of MDM4, which are also maintained by CDK9 activity. In summary, we show that CDK9 activity is essential for the maintenance of high levels of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4.

• MeSH
• cyklin-dependentní kinasa 9 antagonisté a inhibitory   metabolismus   MeSH
• genetická transkripce MeSH
• imidazoly farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• melanom genetika   metabolismus   patologie   MeSH
• MFC-7 buňky MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prsu genetika   metabolismus   patologie   MeSH
• piperaziny farmakologie   MeSH
• pluripotentní kmenové buňky metabolismus   MeSH
• proteiny buněčného cyklu biosyntéza   genetika   metabolismus   MeSH
• protoonkogenní proteiny c-mdm2 biosyntéza   genetika   metabolismus   MeSH
• protoonkogenní proteiny biosyntéza   genetika   metabolismus   MeSH
• roskovitin farmakologie   MeSH
• sulfonamidy farmakologie   MeSH
• synergismus léků MeSH
• transfekce MeSH
• triaziny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• atuveciclib MeSH Prohlížeč
• CDK9 protein, human MeSH Prohlížeč
• Cdk9 protein, mouse MeSH Prohlížeč
• cyklin-dependentní kinasa 9 MeSH
• imidazoly MeSH
• inhibitory proteinkinas MeSH
• MDM2 protein, human MeSH Prohlížeč
• Mdm2 protein, mouse MeSH Prohlížeč
• MDM4 protein, human MeSH Prohlížeč
• Mdm4 protein, mouse MeSH Prohlížeč
• nutlin 3 MeSH Prohlížeč
• piperaziny MeSH
• proteiny buněčného cyklu MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• protoonkogenní proteiny MeSH
• roskovitin MeSH
• sulfonamidy MeSH
• triaziny MeSH

p53 missense mutant proteins commonly show increased stability compared to wild-type p53, which is thought to depend largely on the inability of mutant p53 to induce the ubiquitin ligase MDM2. However, recent work using mouse models has shown that the accumulation of mutant p53 occurs only in tumour cells, indicating that stabilization requires additional factors. To clarify the stabilization of p53 mutants in tumours, we analysed factors that affect their folding and degradation. Although all missense mutants that we studied are more stable than wild-type p53, the levels correlate with individual structural characteristics, which may be reflected in different gain-of-function properties. In the absence of Hsp90 activity, the less stable unfolded p53 mutants preferentially associate in a complex with Hsp70 and CHIP (carboxy terminus of Hsp70-interacting protein), and we show that CHIP is responsible for ubiquitination and degradation of these mutants. The demonstration of a complex interplay between Hsp90, Hsp70 and CHIP that regulate the stability of different p53 mutant proteins improves our understanding of the pro-tumorigenic effects of increased Hsp90 activity during multi-stage carcinogenesis. Understanding the roles of Hsp90, Hsp70 and CHIP in cancers may also provide an important avenue through which to target p53 to enhance treatment of human cancers.

• MeSH
• benzochinony farmakologie   MeSH
• ELISA MeSH
• fibroblasty cytologie   metabolismus   MeSH
• imunoblotting MeSH
• imunoprecipitace MeSH
• konformace proteinů MeSH
• kultivované buňky MeSH
• lidé MeSH
• makrocyklické laktamy farmakologie   MeSH
• mutace genetika   MeSH
• myši knockoutované MeSH
• myši MeSH
• nádorový supresorový protein p53 chemie   fyziologie   MeSH
• nádory genetika   metabolismus   patologie   MeSH
• proteiny tepelného šoku HSC70 genetika   metabolismus   MeSH
• proteiny tepelného šoku HSP90 antagonisté a inhibitory   genetika   metabolismus   MeSH
• protoonkogenní proteiny c-mdm2 fyziologie   MeSH
• ubikvitinace MeSH
• ubikvitinligasy genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzochinony MeSH
• makrocyklické laktamy MeSH
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• proteiny tepelného šoku HSC70 MeSH
• proteiny tepelného šoku HSP90 MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• STUB1 protein, human MeSH Prohlížeč
• Stub1 protein, mouse MeSH Prohlížeč
• tanespimycin MeSH Prohlížeč
• ubikvitinligasy MeSH

The most frequent alterations found in astrocytomas are two major groups of signaling proteins: the cell cycle and the growth factor-regulated signaling pathways. The aim of our study was to detect changes in expression of the following proteins: the tumor suppressors PTEN, p53, and p21Waf1/Cip1, glial fibrillary acidic protein (GFAP, as a marker of astroglial differentiation), the phosphorylated form of protein kinase B/Akt (PKB/Akt), which is downstream to the epidermal growth factor receptor (EGFR), and MDM2, which degrades p53. Paraffin-embedded astrocytoma tissue samples from 89 patients were divided into low grade (grade I-II; 42 samples) and high grade astrocytomas (grade III-IV; 47 samples). Mouse monoclonal antibodies against GFAP, PTEN, PKB/Akt phosphorylated on serine 473, EGFR, p53, p21Waf1/Cip1 and MDM2 were used, followed by standard indirect immunohistochemical method. EGFR protein was detected in 29 % of low grade and in 60 % of high grade astrocytomas. The expression of phosphorylated PKB/Akt was found in roughly the same proportions: in 86% of low grade and in 79% of high grade astrocytomas. PTEN was not found in most of astrocytomas, 64% of low grade and 74% of high grade tumors showed no PTEN staining. Overexpression of the mutated form of p53 or loss of p53 expression, however, was found in about 63% in both groups of astrocytomas with no differences between them. GFAP expression was decreased in tumor astrocytes compared to normal astrocytes and this decreased with grading. GFAP positive tumor cells were detected in only 50% of low grade, and 32% of high grade astrocytomas. The level of MDM2 expression was similar in both grades. Loss of p21Waf1/Cip1 expression was shown in 20% of low and in 45% of high grade tumors. In the subgroup of high grade tumors with wild type p53, 86% showed p21Waf1/Cip1 expression, whereas in the subgroup of high grade tumors with altered p53, only 35% displayed p21Waf1/Cip1. We conclude that EGFR expression increases with astrocytoma grading. EGFR activation may subsequently lead to stimulation of the PKB/Akt survival pathway. PTEN defects may also participate in aggressive tumor behaviour through activation of the PKB/Akt pathway. The alteration of p53 supports the finding that the cell cycle regulation is also disrupted during development of astrocytomas. The changes in PTEN and p53 expression, and activation of PKB/Akt are events in the early stages of astrocytomagenesis. EGFR is one of the factors, which drives the progression of astrocytomas from low to high grade stage.

• MeSH
• astrocytom metabolismus   patologie   MeSH
• buněčný cyklus * MeSH
• dospělí MeSH
• erbB receptory metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• fosfohydroláza PTEN metabolismus   MeSH
• fosforylace MeSH
• gliový fibrilární kyselý protein metabolismus   MeSH
• inhibitor p21 cyklin-dependentní kinasy metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mutace genetika   MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• oligodendrogliom metabolismus   patologie   MeSH
• progrese nemoci MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• protoonkogenní proteiny c-mdm2 metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• erbB receptory MeSH
• fosfatidylinositol-3-kinasy MeSH
• fosfohydroláza PTEN MeSH
• gliový fibrilární kyselý protein MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• MDM2 protein, human MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny c-mdm2 MeSH
• PTEN protein, human MeSH Prohlížeč