The document discusses various topics related to DNA methylation and its roles in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
Nrf2 Transcription Factor- Nuclear Factor- Erythroid 2 related factor)PHARMA IQ EDUCATION
1. Nrf2- transcription factor
2. Reactive Oxygen Species
3. Free Radicals
4. Antioxidant Defence Mechanism
5. Function of Nrf2 receptor
6. Protein structural domain of Nrf2
7. Protein structural domain of Keap1
8. Physiological Role pf Nrf2
9.
THANK YOU
Plant epigenetic memory in plant growth behavior and stress response. Sally M...CIAT
Speaker: Sally Mackenzie, Lloyd and Dottie Huck Chair for Functional Genomics, Department of Biology, Pennsylvania State University. Fellow in the American Society of Plant Biologists and the American Association for the Advancement of Science (AAAS).
Event: Robert D. Havener Seminar on “Innovations for Crop Productivity”.
http://ciat.cgiar.org/event/robert-d-havener-seminar-on-innovations-for-crop-productivity/
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
Nrf2 Transcription Factor- Nuclear Factor- Erythroid 2 related factor)PHARMA IQ EDUCATION
1. Nrf2- transcription factor
2. Reactive Oxygen Species
3. Free Radicals
4. Antioxidant Defence Mechanism
5. Function of Nrf2 receptor
6. Protein structural domain of Nrf2
7. Protein structural domain of Keap1
8. Physiological Role pf Nrf2
9.
THANK YOU
Plant epigenetic memory in plant growth behavior and stress response. Sally M...CIAT
Speaker: Sally Mackenzie, Lloyd and Dottie Huck Chair for Functional Genomics, Department of Biology, Pennsylvania State University. Fellow in the American Society of Plant Biologists and the American Association for the Advancement of Science (AAAS).
Event: Robert D. Havener Seminar on “Innovations for Crop Productivity”.
http://ciat.cgiar.org/event/robert-d-havener-seminar-on-innovations-for-crop-productivity/
KDM5 epigenetic modifiers as a focus for drug discoveryChristopher Wynder
A summary presentation of my scientific work.
My laboratory focused on an enzyme KDM5b (aka PLU-1, JARID1b) that was widely expressed during development and played a key role in progression of breast cancer through HER-2.
My lab focused on understanding the key biochemical activity of the enzyme through dissecting the proteomic and genomic interactors.
Our results were confirmed through the use of ES cells, adult stem cells and mouse models.
Much of this work remains unpublished, please contact me for more information and/or access to any reagents that I still have as part of this work.
crwynder@gmail.com
Sequencing based approaches for profiling dna methylationsciencelearning123
DNA methylation, one of the most studied epigenetic modifications, refers to the addition of a methyl group to the fifth carbon of cytosine (C) catalyzed by DNA methyltransferases (Dnmts), forming 5-methylcytosine (5mC). DNA methylation predominantly occurs in CpGs but is also found in non-CpG contexts.
brief overview on oligonucleotide, oligonucleoside and its application in medicine. given the basic knowledge as well about the DNA and its composition.
WDR7 up-regulation upon knocking down of neighboring noncoding RNA using siRN...Vahid Erfani-Moghadam
Objective(s): Breast cancer is the second leading cause of cancer death in females. Understanding molecular mechanisms in cancer cells compared with normal cells is crucial for diagnostic and therapeutic strategies. Long intergenic non-protein coding RNA, a regulator of reprogramming (lincRNA-RoR) is a noncoding RNA which initially was detected in induced pluripotent stem cells, and it has an important role in cell reprogramming and highly expressed in breast cancer cells. A key point in successful gene silencing is the usage of siRNA delivery system that is safe and efficient. Materials and Methods: In this study, the fifth-generation of PAMAM dendrimer is used as a nanocarrier for entering siRNA molecules for gene silencing of lincRNA-RoR. WDR7 is the gene encoding adjacent of lincRNA-RoR, which has an important role in apoptosis and cell cycle. Gel retardation assay was used to find the best Negative/Positive (N/P) molar charge ratio of siRNA- PAMAM transfected into MDA-MB 231 cells. MTT assay was performed 24 hr after transfection revealed the IC50 value (half maximal inhibitory concentrations) about 100 nanomolar for lincRNA-ROR siRNA. Results: The lincRNA-RoR and WDR7 gene expression changes were evaluated by real-time PCR after siRNA treatment and showed an increase in the gene expression of WDR7. Conclusion: This study showed that PAMAM dendrimer G5/ siRNA could be a useful system delivery for future gene therapy approaches.
SiRNA Delivery for Cancer Therapy: Challenges and Future Perspective by Suvadeep Sen in Advancements in Bioequivalence & Bioavailability
https://crimsonpublishers.com/abb/fulltext/ABB.000518.php
Sequencing based approaches for profiling dna methylationsciencelearning123
DNA methylation, one of the most studied epigenetic modifications, refers to the addition of a methyl group to the fifth carbon of cytosine (C) catalyzed by DNA methyltransferases (Dnmts), forming 5-methylcytosine (5mC). DNA methylation predominantly occurs in CpGs but is also found in non-CpG contexts.
brief overview on oligonucleotide, oligonucleoside and its application in medicine. given the basic knowledge as well about the DNA and its composition.
WDR7 up-regulation upon knocking down of neighboring noncoding RNA using siRN...Vahid Erfani-Moghadam
Objective(s): Breast cancer is the second leading cause of cancer death in females. Understanding molecular mechanisms in cancer cells compared with normal cells is crucial for diagnostic and therapeutic strategies. Long intergenic non-protein coding RNA, a regulator of reprogramming (lincRNA-RoR) is a noncoding RNA which initially was detected in induced pluripotent stem cells, and it has an important role in cell reprogramming and highly expressed in breast cancer cells. A key point in successful gene silencing is the usage of siRNA delivery system that is safe and efficient. Materials and Methods: In this study, the fifth-generation of PAMAM dendrimer is used as a nanocarrier for entering siRNA molecules for gene silencing of lincRNA-RoR. WDR7 is the gene encoding adjacent of lincRNA-RoR, which has an important role in apoptosis and cell cycle. Gel retardation assay was used to find the best Negative/Positive (N/P) molar charge ratio of siRNA- PAMAM transfected into MDA-MB 231 cells. MTT assay was performed 24 hr after transfection revealed the IC50 value (half maximal inhibitory concentrations) about 100 nanomolar for lincRNA-ROR siRNA. Results: The lincRNA-RoR and WDR7 gene expression changes were evaluated by real-time PCR after siRNA treatment and showed an increase in the gene expression of WDR7. Conclusion: This study showed that PAMAM dendrimer G5/ siRNA could be a useful system delivery for future gene therapy approaches.
SiRNA Delivery for Cancer Therapy: Challenges and Future Perspective by Suvadeep Sen in Advancements in Bioequivalence & Bioavailability
https://crimsonpublishers.com/abb/fulltext/ABB.000518.php
Role of notch signalling in deveopment, cancer development and its detailed cancer cell line study for purpose of detailed targetted molecular therapeutics
Cancer Epigenetics: Concepts, Challenges and PromisesMrinmoy Pal
The presentation highlights how recent investigations have shown extensive reprogramming of almost every component of the epigenetic machinery in cancer leading to the emergence of the promising field of epigenetic therapy.
Protein targets in Mycobacterium tuberculosis and their inhibitors for therap...Souparnika Sreelatha
Advancement in the area of anti-tubercular drug development has been full-fledged, yet, a very less number of
drug molecules have reached phase II clinical trials, and therefore “End-TB” is still a global challenge. Inhibitors
to specific metabolic pathways of Mycobacterium tuberculosis (Mtb) gain importance in strategizing antituberculosis
drug discovery. The lead compounds that target DNA replication, protein synthesis, cell wall
biosynthesis, bacterial virulence and energy metabolism are emerging as potential chemotherapeutic options
against Mtb growth and survival within the host. In recent times, the in silico approaches have become most
promising tools in the identification of suitable inhibitors for specific protein targets of Mtb. An update in the
fundamental understanding of these inhibitors and the mechanism of interaction may bring hope to future
perspectives in novel drug development and delivery approaches. This review provides a collective impression of
the small molecules with potential antimycobacterial activities and their target pathways in Mtb such as cell wall
biosynthesis, DNA replication, transcription and translation, efflux pumps, antivirulence pathways and general
metabolism. The mechanism of interaction of specific inhibitor with their respective protein targets has been
discussed. The comprehensive knowledge of such an impactful area of research would essentially reflect in the
discovery of novel drug molecules and effective delivery approaches. This narrative review encompasses the
knowledge of emerging targets and promising chemical inhibitors that could potentially translate in to the anti-
TB-drug discovery.
This ppts is based upon the recent adavancement and methodology about mitochondrial transformation. What is organellar transformation and what is the importance in contemporary time.
Neuro-symbolic is not enough, we need neuro-*semantic*Frank van Harmelen
Neuro-symbolic (NeSy) AI is on the rise. However, simply machine learning on just any symbolic structure is not sufficient to really harvest the gains of NeSy. These will only be gained when the symbolic structures have an actual semantics. I give an operational definition of semantics as “predictable inference”.
All of this illustrated with link prediction over knowledge graphs, but the argument is general.
JMeter webinar - integration with InfluxDB and GrafanaRTTS
Watch this recorded webinar about real-time monitoring of application performance. See how to integrate Apache JMeter, the open-source leader in performance testing, with InfluxDB, the open-source time-series database, and Grafana, the open-source analytics and visualization application.
In this webinar, we will review the benefits of leveraging InfluxDB and Grafana when executing load tests and demonstrate how these tools are used to visualize performance metrics.
Length: 30 minutes
Session Overview
-------------------------------------------
During this webinar, we will cover the following topics while demonstrating the integrations of JMeter, InfluxDB and Grafana:
- What out-of-the-box solutions are available for real-time monitoring JMeter tests?
- What are the benefits of integrating InfluxDB and Grafana into the load testing stack?
- Which features are provided by Grafana?
- Demonstration of InfluxDB and Grafana using a practice web application
To view the webinar recording, go to:
https://www.rttsweb.com/jmeter-integration-webinar
Slack (or Teams) Automation for Bonterra Impact Management (fka Social Soluti...Jeffrey Haguewood
Sidekick Solutions uses Bonterra Impact Management (fka Social Solutions Apricot) and automation solutions to integrate data for business workflows.
We believe integration and automation are essential to user experience and the promise of efficient work through technology. Automation is the critical ingredient to realizing that full vision. We develop integration products and services for Bonterra Case Management software to support the deployment of automations for a variety of use cases.
This video focuses on the notifications, alerts, and approval requests using Slack for Bonterra Impact Management. The solutions covered in this webinar can also be deployed for Microsoft Teams.
Interested in deploying notification automations for Bonterra Impact Management? Contact us at sales@sidekicksolutionsllc.com to discuss next steps.
The Art of the Pitch: WordPress Relationships and SalesLaura Byrne
Clients don’t know what they don’t know. What web solutions are right for them? How does WordPress come into the picture? How do you make sure you understand scope and timeline? What do you do if sometime changes?
All these questions and more will be explored as we talk about matching clients’ needs with what your agency offers without pulling teeth or pulling your hair out. Practical tips, and strategies for successful relationship building that leads to closing the deal.
Accelerate your Kubernetes clusters with Varnish CachingThijs Feryn
A presentation about the usage and availability of Varnish on Kubernetes. This talk explores the capabilities of Varnish caching and shows how to use the Varnish Helm chart to deploy it to Kubernetes.
This presentation was delivered at K8SUG Singapore. See https://feryn.eu/presentations/accelerate-your-kubernetes-clusters-with-varnish-caching-k8sug-singapore-28-2024 for more details.
DevOps and Testing slides at DASA ConnectKari Kakkonen
My and Rik Marselis slides at 30.5.2024 DASA Connect conference. We discuss about what is testing, then what is agile testing and finally what is Testing in DevOps. Finally we had lovely workshop with the participants trying to find out different ways to think about quality and testing in different parts of the DevOps infinity loop.
Software Delivery At the Speed of AI: Inflectra Invests In AI-Powered QualityInflectra
In this insightful webinar, Inflectra explores how artificial intelligence (AI) is transforming software development and testing. Discover how AI-powered tools are revolutionizing every stage of the software development lifecycle (SDLC), from design and prototyping to testing, deployment, and monitoring.
Learn about:
• The Future of Testing: How AI is shifting testing towards verification, analysis, and higher-level skills, while reducing repetitive tasks.
• Test Automation: How AI-powered test case generation, optimization, and self-healing tests are making testing more efficient and effective.
• Visual Testing: Explore the emerging capabilities of AI in visual testing and how it's set to revolutionize UI verification.
• Inflectra's AI Solutions: See demonstrations of Inflectra's cutting-edge AI tools like the ChatGPT plugin and Azure Open AI platform, designed to streamline your testing process.
Whether you're a developer, tester, or QA professional, this webinar will give you valuable insights into how AI is shaping the future of software delivery.
GDG Cloud Southlake #33: Boule & Rebala: Effective AppSec in SDLC using Deplo...James Anderson
Effective Application Security in Software Delivery lifecycle using Deployment Firewall and DBOM
The modern software delivery process (or the CI/CD process) includes many tools, distributed teams, open-source code, and cloud platforms. Constant focus on speed to release software to market, along with the traditional slow and manual security checks has caused gaps in continuous security as an important piece in the software supply chain. Today organizations feel more susceptible to external and internal cyber threats due to the vast attack surface in their applications supply chain and the lack of end-to-end governance and risk management.
The software team must secure its software delivery process to avoid vulnerability and security breaches. This needs to be achieved with existing tool chains and without extensive rework of the delivery processes. This talk will present strategies and techniques for providing visibility into the true risk of the existing vulnerabilities, preventing the introduction of security issues in the software, resolving vulnerabilities in production environments quickly, and capturing the deployment bill of materials (DBOM).
Speakers:
Bob Boule
Robert Boule is a technology enthusiast with PASSION for technology and making things work along with a knack for helping others understand how things work. He comes with around 20 years of solution engineering experience in application security, software continuous delivery, and SaaS platforms. He is known for his dynamic presentations in CI/CD and application security integrated in software delivery lifecycle.
Gopinath Rebala
Gopinath Rebala is the CTO of OpsMx, where he has overall responsibility for the machine learning and data processing architectures for Secure Software Delivery. Gopi also has a strong connection with our customers, leading design and architecture for strategic implementations. Gopi is a frequent speaker and well-known leader in continuous delivery and integrating security into software delivery.
UiPath Test Automation using UiPath Test Suite series, part 4DianaGray10
Welcome to UiPath Test Automation using UiPath Test Suite series part 4. In this session, we will cover Test Manager overview along with SAP heatmap.
The UiPath Test Manager overview with SAP heatmap webinar offers a concise yet comprehensive exploration of the role of a Test Manager within SAP environments, coupled with the utilization of heatmaps for effective testing strategies.
Participants will gain insights into the responsibilities, challenges, and best practices associated with test management in SAP projects. Additionally, the webinar delves into the significance of heatmaps as a visual aid for identifying testing priorities, areas of risk, and resource allocation within SAP landscapes. Through this session, attendees can expect to enhance their understanding of test management principles while learning practical approaches to optimize testing processes in SAP environments using heatmap visualization techniques
What will you get from this session?
1. Insights into SAP testing best practices
2. Heatmap utilization for testing
3. Optimization of testing processes
4. Demo
Topics covered:
Execution from the test manager
Orchestrator execution result
Defect reporting
SAP heatmap example with demo
Speaker:
Deepak Rai, Automation Practice Lead, Boundaryless Group and UiPath MVP
Encryption in Microsoft 365 - ExpertsLive Netherlands 2024Albert Hoitingh
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Kubernetes & AI - Beauty and the Beast !?! @KCD Istanbul 2024Tobias Schneck
As AI technology is pushing into IT I was wondering myself, as an “infrastructure container kubernetes guy”, how get this fancy AI technology get managed from an infrastructure operational view? Is it possible to apply our lovely cloud native principals as well? What benefit’s both technologies could bring to each other?
Let me take this questions and provide you a short journey through existing deployment models and use cases for AI software. On practical examples, we discuss what cloud/on-premise strategy we may need for applying it to our own infrastructure to get it to work from an enterprise perspective. I want to give an overview about infrastructure requirements and technologies, what could be beneficial or limiting your AI use cases in an enterprise environment. An interactive Demo will give you some insides, what approaches I got already working for real.
Knowledge engineering: from people to machines and back
Lezione 2 2008 09
1. CORSO DI LAUREA SPECIALISTICA IN BIOTECNOLOGIE DEL
FARMACO
Adriana Maggi
BIOTECNOLOGIE FARMACOLOGICHE
2008/09
LEZIONE 2
2. I PROCESSI DI METILAZIONE GIOCANO UN RUOLO
NELLA PATOGENESI UMANA
3. methyl DNA binding protein 2 (MeCP2)
The mechanism(s) by which the native MeCP2 protein operates in the
cell are not well understood.
Historically, MeCP2 has been characterized as a proximal gene
silencer with 2 functional domains:
1. a methyl DNA binding domain and
2.a transcription repression domain.
However, several lines of new data indicate that MeCP2 structure and
function relationships are more complex: an analysis of cell-based
experiments suggesting MeCP2 is a regulator, rather than a strict
silencer, of transcription. The new data establish MeCP2 as a
multifunctional nuclear protein, with potentially important roles in
chromatin architecture, regulation of RNA splicing, and active
transcription..
4. SINDROME DI RETT
Andreas Rett, che aveva osservato un comportamento insolito, tragico e affascinante insieme,
in alcune bambine sedute nella sala d'aspetto del suo studio. Correva l'anno 1966.
Nel 1999, il team di Huda Zoghbi del Baylor College of Medicine di Houston scoprì che la
sindrome di Rett è associata a una mutazione del gene MeCP2, localizzato sul cromosoma X. Il
gene MeCP2 è un repressore della trascrizione genica.
La proteina MeCP2 è espressa in modo predominante nei neuroni maturi. MeCP2 modula le
connessioni sinaptiche e quindi la comunicazione cellulare attraverso la regolazione di alcuni
geni, tra cui il brain-derived neurotrophic factor (BDNF).
Guy et al., con un sistema murino molto sofisticato hanno silenziato la sintesi
della proteina MeCP2 causando la patologia, poi ne hanno reinstaurato la
sintesi con una remissione della sintomatologia
Più recentemente, si è visto che le MeCP2 interagisce con la proteina YB-1
che è coinvolta nella matutazione degli RNA e in particolare della subunità
NR1 dei recettori per il glutammato NMDA
Guy J, Gan J, Selfridge J, Cobb S, Bird A. Reversal of neurological defects in
a mouse model of Rett syndrome. Science 2007; 315:1143-1147
6. METILAZIONE DEL DNA E CANCRO
The alterations of DNA methylation level and
patterns are a common feature of human cancer
cells. A global DNA hypomethylation has been
observed in many cancers, without obvious
sequence specificity
Recently, an extensive study of about 1200 CpG islands has
indicated that hypermethylated CpG islands are not randomly
distributed and the patterns of the hypermethylation might
be specific of subclasses of cancers.
The methylation status of tumor suppressor genes has been
extensively investigated and such alterations have been
reported in many human tumors (Robertson and Jones,
2000).
7. METILAZIONE DEL DNA E CANCRO
Several reports link genome hypomethylation to
genome instability. In particular, it was shown
recently that strongly reduced DNMT activity in a
transgenic mouse model caused demethylation of
centromeric satellite and other repeat sequences,
which resulted in a variety of chromosome defects
and concomitant tumorigenesis
8. Figure 1. Epigenetic cancer therapy. DNA methyltransferases (DNMTs) can
cause ectopic methylation and gene silencing. These events are called
epimutations and promote tumorigenesis if directed to tumor suppressor
genes. Importantly, the maintenance of epimutations requires the continuous
activity of DNMTs. This accounts for the principal reversibility of
epimutations by DNMT inhibitors.
9. Il mantenimento della metilazione del
DNA (da parte di DNMT1) è
indispensabile nella duplicazione del DNA
per mantenere metilati specifiche porzioni
del DNA.
Nel topo la mutazione di DNMT1 è letale
10. Human DNA methyltransferases (DNMTs) and their functionally important
domains.
All known DNMTs share a highly conserved C-terminal catalytic domain.
The N-terminal domains differ strongly between DNMT1 and DNMT3 enzymes
and contain several motifs for regulatory functions: a PCNA binding domain
(PBD), a replication foci targeting domain (RFTD), a CXXC domain implicated in
DNA binding, a PWWP domain linked to protein targeting and an ATRX domain
implicated in histone deacetylase interactions.
The DNMT3A and DNMT3B proteins are similar and are probably the products
of a recent gene duplication event.
11. 5-Azacytidine (Vidazae) has been approved
for the treatment of myelodysplastic
syndrome.
This has been a major milestone in the
field of cancer epigenetics and provides an
important validation for the concept of an
epigenetic cancer therapy
12.
13. Deacetilasi istoniche: una nuova classe di farmaci
nella terapia antitumorale
Generalmente agiscono causando apoptosi di
cellule tumorali,
ma non di cellule non tumorali; le HDAC sono
generalmente associate a fattori di trascrizione
oncogeni.
14. The effects of HDAC inhibitors on gene expression are highly selective,
leading to transcriptional activation of certain genes such as the cyclindependent kinase inhibitor p21WAF1/CIP1 but repression of others.
HDAC inhibition not only results in acetylation of histones but also
transcription factors such as p53, GATA-1 and estrogen receptor-alpha.
The functional significance of acetylation of non-histone proteins and the
precise mechanisms whereby HDAC inhibitors induce tumor cell growth
arrest, differentiation and/or apoptosis are currently the focus of
intensive research.
Several HDAC inhibitors have shown impressive antitumor activity in vivo
with remarkably little toxicity in preclinical studies and are currently in
phase I clinical trial.
15. Classificazione delle deacetilasi istoniche
HDACs are classified in four groups based on their homology to
yeast histone deacetylases:
Class I which includes HDAC1, -2, -3 and -8 are related to yeast
RPD3 gene;
Class II which includes HDAC4, -5, -6, -7, -9 and -10 are related
to yeast Hda1 gene;
Class III, also known as the sirtuins are related to the Sir2 gene
and include SIRT1-7, and
Class IV which contains only HDAC11 has features of both Class I
and II.
16. Classificazione degli inibitori delle istone deacetilasi
The “classical” HDIs act exclusively on Class I and Class II HDACs by
binding to the zinc containing catalytic domain of the HDACs. These
classical HDIs fall into several groupings, in order of decreasing
potency:
(i) hyroxamic acids, such as Tricostatine A,
(ii) cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
(iii) benzamides,
(iv) electrophilic ketones, and
(v) the alophatic acid compounds such as phenylbutyrate and valproic
acid.
"Second generation" HDIs include SAHA/Vorinostat,
Belinostat/PXD101, MS275, LAQ824/LBH589, CI994, and
MGCD0103.
The sirtuin Class III HDACs are NAD+ dependent and are therefore
inhibited by nicotinamides, as well derivatives of NAD,
dihydrocoumarin, naphthopyranone, and 2-hydroxynaphaldehydes.[4]
17. O
N
H
N
N-hydroxy-N'-phenyl-octanediamide
O
H
OH
VORINOSTAT (Zolinza) è il primo inibitore delle acetilasi
istoniche approvato per il trattamento di neoplasie
Nel 2006 il VORINOSTAT è stato approvato per il
trattamento del linfoma a cellule T cutaneo
Esistono studi preclinici che indicano una attività
antinfiammatoria del vorinostat
Nel 2007 ricerche presso la Mayo Clinics hanno dimostrato
che il Vorinostat è efficace nel glioblastoma ricorrente
18. HDAC inhibitors can activate both the deathreceptor and intrinsic apoptotic pathways
19. Histone deacetylase inhibitors as therapeutics for polyglutamine
disorders Rachel Butler and Gillian P. Bates
Nature Reviews Neuroscience 7, 784-796 (October 2006)
20. P53
P53 puo’ agire a diversi livelli:
Puo’ attivare proteine per il riparo
del DNA
Puo’ regolar e la duplicazione
cellulare a livello G1/S
Puo’ iniziare processi apoptotici
23. Il ruolo degli INSULATORS nella regolazione della
espressione genica
Es. i geni globinici e LCR HS4,
scs di Drosophila che isolano hsp70)
In genere sono sequenze ricche di isole CpG non metilate
Ci sono proteine che legano gli insulators
24. Transcription factors are associated with the nuclear matrix. It
has been proposed that the nuclear matrix recruits
transcription factors, facilitating their interaction with
regulatory DNA elements.
25. ESPRESSIONE GENICA IN EUCARIOTE: SEQUENZA DI EVENTI
3’
RNA, trascritto primario
Capping e poliadenilazione
TRASCRIZIONE
MODIFICAZ.
TP
Splicing o maturazione
Fuoriuscita dal nucleo
riconoscimento da parte dei ribosomi
traduzione
TRADUZIONE
Modificazioni post-traduzionali
Editor's Notes
a | MECP2 (methyl-CpG-binding protein 2) gene structure. The positions and frequencies of the most common mutations that are associated with Rett syndrome in females are indicated. b | The two main protein isoforms, MeCP2A (486 amino acids) and MeCP2B (498 amino acids), are produced by alternative splicing of the MECP2 transcript and differ in their N-terminal regions, which are encoded by exon 2 of the gene in the case of MeCP2A and exon 1 in MeCP2B. MBD, methyl-CpG binding domain; NLS, nuclear localization signal; poly(A), polyadenylation; TRD, transcriptional repression domain; X, stop codon.
HDAC inhibitors can activate both the death-receptor and intrinsic apoptotic pathways. The death-receptor pathway is triggered by the ligation of death receptors, which results in binding of adaptor proteins (FADD) and the recruitment and activation of membrane-proximal activator caspases (caspase-8). These caspases in turn activate downstream effector caspases (caspase-3). The intrinsic apoptotic pathway is activated by internal stresses that induce mitochondrial membrane disruption mediated by pro-apoptotic BCL2 proteins (BAX/BAK). HDAC inhibitors can induce the activation of the intrinsic apoptotic pathway, and anti-apoptotic BCL2 proteins inhibit mitochondrial membrane damage. HDAC inhibitors might still induce cell death in the absence of caspase activation after the production of reactive oxygen species (ROS). Asterix's denote components of the death pathways that are affected by HDAC inhibitors. Those components that inhibit cell death are shown in yellow, and those that promote death are in purple. BAK, BCL2 antagonist/killer protein; BAX, B-cell-associated X protein; BCL2, B-cell lymphoma 2; Cyto c, cytochrome c; FADD, FAS-associated via death domain; HTRA2, high temperature requirement 2.
The function of non-histone proteins is also affected by acetylation (Ac)/deacetylation at specific lysine residues (K). Therefore, histone deacetylase (HDAC) inhibitors could have far reaching effects on multiple cellular processes. Two examples of non-histone acetylated proteins that might be affected by HDAC inhibition and involved in Huntington's disease and other polyglutamine repeat diseases are p53 and heat shock protein 90 (HSP90). a | p53 is acetylated under conditions of stress or HDAC inhibition by its cofactor CREB binding protein (CBP). Acetylation increases p53 activity by enhancing its stability and DNA binding activity. The end result is upregulated expression of p53-controlled genes, such as HTT. b | HSP90 is a chaperone that complexes with other chaperones, such as p23, to maintain correct conformational folding of is client proteins. HDAC6 deacetylates HSP90; inhibition of HDAC6 would result in hyperacetylated HSP90, which would be unable to interact with its co-chaperones and properly fold its client proteins. Inhibition of HDACs in this pathway would therefore lead to misfolded client proteins being targeted for degradation via the ubiquitin–proteasome system. HAT, histone acetyltransferase.