The document presents information on PTEN and the PI3-kinase pathway in cancer. It discusses how PTEN acts as a tumor suppressor by negatively regulating the PI3-kinase pathway, which promotes cell growth and survival. Mutations or deletions of the PTEN gene are common in many cancer types as they lead to overactivation of the PI3-kinase pathway. The document outlines the signaling events in the PI3-kinase pathway, how PTEN regulates it, additional functions of PTEN, and potential cancer therapeutics that target this pathway.
MAPK Signaling pathway (Mitogen-activated protein kinase), how the pathway helps in regulation of mitosis, It's activation and inactivation inside the cell, roles of MAPK pathway in cancerous cell, different classes of MAP kinase in human
MAPK Signaling pathway (Mitogen-activated protein kinase), how the pathway helps in regulation of mitosis, It's activation and inactivation inside the cell, roles of MAPK pathway in cancerous cell, different classes of MAP kinase in human
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
Majority of cancer lead by point mutation in p53 gene. which is also known as "guardian of genome". this mutation leads conversion of normal cell into cancerous cell.
Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another.
This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades.
In these signal transduction pathways, there are often shared components that can interact with either pathway.
A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
Majority of cancer lead by point mutation in p53 gene. which is also known as "guardian of genome". this mutation leads conversion of normal cell into cancerous cell.
Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another.
This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades.
In these signal transduction pathways, there are often shared components that can interact with either pathway.
A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.
Regulation of pten activity by its carboxyl terminal autoinhibitoryChau Chan Lao
Regulation of PTEN Activity by Its Carboxyl-terminal Autoinhibitory Domain.
Leticia Odriozola, Gobind Singh, Thuong Hoang, and Andrew M. Chan
From the Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, 10029
THE JOURNAL OF BIOLOGICAL CHEMISTRY, VOL. 282, NO. 32, pp. 23306–23315, August 10, 2007
目前已知PTEN(Phosphatase and tensin homolog)是腫瘤抑制蛋白,其由403個氨基酸組成,主要分PTPase及C2 domain,C2 domain使PTEN可與細胞膜作用連結。
PTEN之C-tail(aa 350~403)被發現具有調控PTEN自身活性之功能。前人研究指出C-tail有6個可磷酸化之位置(Thr-366、Ser-370、Ser-380、Thr-382、Thr-383及Ser-385),這些位置可調控PTEN之腫瘤抑制能力、胞內之分佈及穩定性。前人產生以上位置突變之PTEN變異株,發現這些變異株具有更強的腫瘤抑制能力,但穩定性將降低,這可能是因這些變異株具有更開放結構所致。
本報告針對研究PTEN C-tail在連結細胞膜和在其本身催化活性中扮演的功能。作者先產生一系列之PTEN磷酸化位置變異株,發現S385A會促使PTEN之membrane localization in vivo及加強phosphatase活性in vitro,而且此突變會使Ser-380/Thr-382/Thr-383 cluster的磷酸化程度降低,因此知Ser-385可透過被去磷酸化以調控PTEN。而以phosphomimic residues取代Ser-380/Thr-382/Thr-383會使上述S385A所產生之PTEN催化活性反轉。之後利用免疫沉澱方法,發現C-tail之71-amino acid region會與C2 domain上之CBR3 motif作用,暗示C-tail參與連結細胞膜之調控。最後利用合成之PTEN C-tail peptide,發現其可抑制PTEN之催化活性in vitro,而在細胞表現此peptide則會抑制PTEN之membrane localization,磷酸化之Akt量亦上升。以上實驗顯示C-tail在PTEN之membrane recruitment及PTPase活性調控中扮演Autoinhibitory domain角色。
A journal club style presentation on a publication about the effect of microRNAs and pseudogenes on tumor gene regulation.
(Note: The animations in the slides do not work on SlideShare, please download the PowerPoint file to view.)
Alex Rosenberg is an Intensivist who was working in a transplant centre last year. He gave this talk on immunosupression at last year's Bedside Critical Care Conference and managed to make a fairly dry subject seem understandable and relevant. Go to www.intensivecarenetwork.com for the podcast.
Molecular signaling involved in breast cancerainnie babarrr
Molecular signaling is very important to predict patient's clinical outcome. HER signaling is most important one, by its regulation cascade of pathways started. So, by understanding proteins over-expression we can target with inhibitors to suppress particular protein, which will results in treatment of breast cancer or Drug discovery.
Essence of PTEN: a Broad-Spectrum Therapeutic Target in Cancer Dr Varruchi Sharma
The levels of protein tyrosine phosphorylation within a cell is regulated by protein tyrosine kinases and protein tyrosine phosphatases. These protein tyrosine phosphatases (PTP) can act both as positive and negative regulators during cell cycle progression and signal transduction. Phosphatase activity is shown by Phosphatase and Tensin homolog (PTEN) protein encoded by PTEN gene localized on human chromosome 10. Earlier findings established the role of PTEN as a tumor suppressor in Cowden’s disease, where PTEN mutations resulted in disease outcomes. Subsequent studies found the role of PTEN mutations in various human cancers, making it one of the vastly studied tumor suppressor genes. The current review has been planned to get a deeper insight into the potential role of PTEN in a variety of physiological processes involved in normal development like cell growth, migration, and differentiation along with the factors, regulation, and underlying mechanism
Mitochondria are double membranous organelle, the inner membrane is more larger than the outer one. For this reason the inner membrane of the mitochondria folds inside forming a special figure called creasteae. The inner mitochondrial membrane (IMM) contains the subunits for oxidative phosphorylation (OXPHOS). And this inner mitochondrial membrane coverd by a second membrane called the outer mitochondrial membrane (OMM). We called mitochondria as a power house of cell not only they generates ATP via oxidative phosphorylation they also take part in various biochemical pathways such as- pyrimidine and purine biosynthesis, heme biosynthesis, the regulation of N2 balance in urea cycle, gluconeogenesis, keton body production and fatty acid degradation and elongation. They also take part in cell signalling via regulating the protein-protein interaction or by regulating the cellular concentration of calcium ion(Ca2+) and reactive oxygen species(ROS).
During various biological diseasesmitochondrial morphology altered, as in the case when there is lack of nutrient in our body mitochondria combine together to share their nutrient and alo their DNA and ETC components to maintain their OXPHOS. But in case of high energy demand of a part of body mitochondria undergo division or called fission because they move rapidly than lager one (Zhao et al., 2013). Fission also occur in mitotic cell to share equal amount of mitochondria to the daughter cells. Many questions arise in mitochondrial dinamics but here I am going to answer a most doubtful question- Is mitochondrial dynamics play any role in tumorigenic process? Is any oncogenic signalling play crucial role in morphological alteration of mitochondria?
This presentation done by omkar kapil a student at NIPER-A basically this presentation is regarding to the discussion of novel target and therapies in the case of pancreatitis from understanding this we can easily attack on the site and from inhibition of of that site we will be beneficial in human welfare
What is greenhouse gasses and how many gasses are there to affect the Earth.moosaasad1975
What are greenhouse gasses how they affect the earth and its environment what is the future of the environment and earth how the weather and the climate effects.
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
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Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
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Toxic effects of heavy metals : Lead and Arsenicsanjana502982
Heavy metals are naturally occuring metallic chemical elements that have relatively high density, and are toxic at even low concentrations. All toxic metals are termed as heavy metals irrespective of their atomic mass and density, eg. arsenic, lead, mercury, cadmium, thallium, chromium, etc.
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In this book, we use conservation of energy techniques on a fluid element to derive the Modified Bernoulli equation of flow with viscous or friction effects. We derive the general equation of flow/ velocity and then from this we derive the Pouiselle flow equation, the transition flow equation and the turbulent flow equation. In the situations where there are no viscous effects , the equation reduces to the Bernoulli equation. From experimental results, we are able to include other terms in the Bernoulli equation. We also look at cases where pressure gradients exist. We use the Modified Bernoulli equation to derive equations of flow rate for pipes of different cross sectional areas connected together. We also extend our techniques of energy conservation to a sphere falling in a viscous medium under the effect of gravity. We demonstrate Stokes equation of terminal velocity and turbulent flow equation. We look at a way of calculating the time taken for a body to fall in a viscous medium. We also look at the general equation of terminal velocity.
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Exposé invité Journées Nationales du GDR GPL 2024
1. PTEN AND THE PI3-KINASE
PATHWAY IN CANCER
PRESENTED BY
BERNARD BAHAAH (PG 4575315)
MPHIL BIOCHEMISTRY
10/6/2016 Bernard Bahaah 1
2. PRESENTATION OUTLINE
• Brief Introduction to cancer
• Signaling through the PI3-Kinase Pathway
• Linking the PI3-Kinase Pathway to Cancer
• Regulation of PTEN-Mediated Tumour Suppression
• Additional Functions of PTEN
• Therapeutic Targeting of the PI3-Kinase Pathway
• Conclusion
10/6/2016 Bernard Bahaah 2
3. CANCER INTRODUCTION
• Cancer refers to a group of diseases involving abnormal and
uncontrolled cell growth.
• There is further spread of these cells to other body parts.
• Some signs and symptoms of cancer are a lump, prolonged
cough, abnormal bleeding, change in bowel movement and
unexplained weight loss.
• There are over a 100 types of cancer
(WHO,2014)
10/6/2016 Bernard Bahaah 3
4. Intro. Cont.
10/6/2016 Bahaah Bernard 4
• In higher eukaryotes the PI3K pathway regulates diverse cellular processes,
including metabolism, survival, proliferation, apoptosis, growth, and cell
migration (Engelman et al., 2006).
• PI3Ks are a family of intracellular lipid kinases that phosphorylate the 3′-
hydroxyl group of phosphatidylinositols and phosphoinositides (Engelman
et al., 2006).
• PI3Ks are grouped into three based on structure and substrate specificity .
These are classes I, II and III (Engelman et al., 2006).
Class I PI3Ks basically phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2)
and phosphatidylinositol-3,4,5-trisphosphate (PIP3).
Class I PI3K may be activated by RTKs or GPCRs leading to Class I A or Class IB
respectively (Engelman et al., 2006).
5. Intro. Cont.
• Class II and class III PI3Ks use phosphatidylinositol (PI) as a substrate to
generate PI-3-P.
• Class II PI3Ks bind clathrin in coated pits, suggesting a function in
membrane trafficking and receptor internalization (Gaidarov et al., 2001).
• There is one class III PI3K in mammals, VPS34, as a sensor of the available
amino acids and signals to mammalian target of rapamycin (mTOR) to
regulate cell growth and autophagy in response to low nutrient
(Gaidarov et al., 2001.
• Research shows that signaling through all classes of PI3K is connected to
key growth-regulatory mechanisms, but it is only class IA PI3ks that have
been implicated in cancer development (Gaidarov et al., 2001).
10/6/2016 Bernard Bahaah 5
7. Signaling Through PI3-Kinase Pathway
• There is initial binding of a ligand to an RTK receptor causing activation.
• Activated PI3Ks catalyze the formation of PIP3 from PIP2, and the lipid
phosphatase PTEN (phosphatase and tensin homolog deleted on
chromosome 10) inhibits the activity of PI3Ks by dephosphorylating
PIP3 into PIP2 (Feng et al., 2004).
• PIP3 transduces activating signals by binding to the pleckstrin
homology (PH) domains of proteins, thereby recruiting them to the
membrane (Feng et al., 2004).
• AKT is recruited to the membrane via PIP3 binding of its PH domain and
is fully activated following phosphorylation by a kinase (Feng et al.,
2004)
10/6/2016 Bernard Bahaah 7
8. Signaling Through PI3-Kinase Pathway
• AKT-mediated phosphorylation of the transcription factor FOXO can
increase proliferation and survival by causing FOXO to be retained
in the cytoplasm (Engelman et al., 2006)..
• TSC1 (hamartin) and TSC2 (tuberin) form a complex that inhibits
activity of the small G protein Rheb (Engelman et al., 2006).
• AKT-mediated phosphorylation of TSC2 relieves its inhibition of
Rheb activity, leading to activation of the rapamycin-sensitive mTOR
complex mTORC1. mTORC1 activity promotes growth through
upregulation of protein synthesis (Engelman et al., 2006).
10/6/2016 Bernard Bahaah 8
9. Signaling Through PI3-Kinase Pathway
• PTEN, TSC1, TSC2, and LKB1 are all tumor-suppressor genes that
negatively regulate mTORC1 activity. Mutations in these genes can result
in varied number of health conditions including cancer (Zbuk and Eng,
2007)).
• Akt-mediated phosphorylation has been found to enhance activity of NF-kB
which promotes degradation of P53 (Zbuk and Eng, 2007).
• AKT can regulate multiple targets that promote aerobic glycolysis, a
metabolic feature of many cancer cells (DeBerardinis et al., 2008).
• PIP3 also influences cell motility by signaling through Rac and Cdc42
(VanHaarstert et al., 2004) a connection that may be relevant to tumor cell
invasion as well as normal developmental roles for PI3K signaling (Chalhoub
and Baker,2009).10/6/2016 Bernard Bahaah 9
10. Linking PI3-Kinase Pathway to Cancer
• A new phosphatase termed PTEN, has been identified
in MMAC (mutated in multiple advanced cancers)
(Chalhoub and Baker, 2009).
• Impaired PTEN function loss leads to PIP3
accumulation in cells and activation of its downstream
signals (slide 6).
• PTEN loss of function has been attributed to
mutations, deletions, transcriptional silencing, or
protein instability at a frequency that can rival p53
alterations
10/6/2016 Bernard Bahaah 10
11. Linking PI3-Kinase Pathway to Cancer
• PTEN somatic mutations occurs in many cancers, with the
highest numbers in endometrium, central nervous system,
skin, and prostate cancers (Chalhoub and Baker, 2009).
• In the CNS, loss of 10q, including PTEN, is found in 70% of
glioblastomas.
• Somatic mutation in the second allele of PTEN, which results
in biallelic inactivation, occurs in 25% to 40% of glioblastomas
(Chalhoub and Baker, 2009).
10/6/2016 Bernard Bahaah 11
12. Linking PI3-Kinase Pathway to Cancer
• Inherited mutation of PTEN causes cancer predisposition, and
both alleles are inactivated (two hits) in sporadic tumors and
in tumors from patients with germline mutations (Chalhoub
and Baker, 2009).
• PTEN germline mutations are found in 80% of CS cases
(Chalhoub and Baker, 2009) .
• CS is an autosomal dominant disorder characterized by
multiple hamartomas and a risk of breast, thyroid, and
endometrial carcinomas. (Chalhoub and Baker, 2009).
10/6/2016 Bernard Bahaah 12
13. REGULATION OF PTEN
• PTEN can be regulated throughposttranslational modifications,
subcellular localization, and binding partners (Chalhaoub and Baker,
2009).
• The crystal structure of PTEN shows that it has a phosphatase
domain and the C2 domain .
• Human PTEN is made up of 403 amino acids and is characterized by
five functional domains a short N-terminal PIP2-binding domain, a
phosphatase domain, a C2 domain, a C-terminal tail containing PEST
(proline, glutamic acid, serine, threonine) sequences and a
postsynaptic density protein.
10/6/2016 Bernard Bahaah 13
14. REGULATION OF PTEN
• For example, the C-terminal tail of PTEN binds to a
number of proteins that are linked totumorigenesis
(Chaloub and Baker, 2009).
10/6/2016 Bernard Bahaah 14
15. REGULATION OF PTEN
• PTEN is modified, and likely regulated, by
multiple posttranslational mechanisms
including;
Phosphorylation
acetylation
oxidation
ubiquitination
10/6/2016 Bernard Bahaah 15
16. REGULATION OF PTEN
• However, in vitro studies have also suggested potential roles
for nuclear PTEN in chromosomal stability, DNA-damage
responses, and cell-cycle regulation (Chaoulhab and Baker,
2009) .
17. ADDITIONAL FUNCTIONS OF PTEN
Some additional functions of PTEN are;
• Genomic Integrity
• Cell Migration
• Stem Cell self renewal
Hence mutations in PTEN will affect the genomic
integrity, cell migration and stem cell self renewal of a
particular cell.
10/6/2016 Bernard Bahaah 17
18. THERAPEUTIC TARGETING OF THE PI3-KINASE PATHWAY
• Use of rapamycin (or its analogs) to block the downstream
consequences (Chalhoub and Baker, 2009).
• There has been further development of multiple inhibitors of
PI3K, including a dualinhibitor of p110α and mTOR termed PI-
103 (Chalhoub and Baker, 2009).
10/6/2016 Bernard Bahaah 18
19. CONCLUSION
• Enough research has substantiated the involvement of PTEN
in PI3-Kinase pathway in cancer development. Whenever
PTEN gets mutated it is likely PI3-Kinase pathway is affected
and that cancer maybe the resultant effect on those cells.
10/6/2016 Bernard Bahaah 19
20. REFERENCES
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