Caspases are cysteine-dependent aspartate specific proteases that cleave target proteins after aspartic acid residues. They exist as inactive zymogens called procaspases in cells and initiate a proteolytic cascade when activated. This leads to cleavage of key proteins and characteristic apoptosis morphology. The Bcl-2 family of proteins regulate apoptosis at the mitochondrial membrane, with pro-apoptotic proteins like Bax activating apoptosis and anti-apoptotic proteins like Bcl-2 inhibiting apoptosis. Many cancers acquire mutations in genes encoding proteins that regulate apoptosis, allowing cancer cells to evade cell death signals and continue uncontrolled proliferation. Targeting apoptosis pathways is a promising strategy for cancer treatment.
Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
Apoptosis is a
-pathway of cell death that is
-induced by an internally regulated program
-in which cells destined to die activate intrinsic enzymes that --degrade the cells’ own nuclear DNA and also nuclear and cytoplasmic proteins
-With minimal host reaction.
Apoptosis also known as cell suicide. Difference between necrosis and apoptosis. Changes in apoptosis. Mechanism of apoptosis. Functional significance of apoptosis. Applied aspects of apoptosis
Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
Apoptosis is a
-pathway of cell death that is
-induced by an internally regulated program
-in which cells destined to die activate intrinsic enzymes that --degrade the cells’ own nuclear DNA and also nuclear and cytoplasmic proteins
-With minimal host reaction.
Apoptosis also known as cell suicide. Difference between necrosis and apoptosis. Changes in apoptosis. Mechanism of apoptosis. Functional significance of apoptosis. Applied aspects of apoptosis
Cell death, particularly apoptosis, is probably one of the
most widely-studied subjects among cell biologists.
Understanding apoptosis in disease conditions is very
important as it not only gives insights into the pathogenesis
of a disease but may also leaves clues on how
the disease can be treated. In cancer, there is a loss of
balance between cell division and cell death and cells
that should have died did not receive the signals to do
so. The problem can arise in any one step along the way
of apoptosis.Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions.
It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of
apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due
to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the
culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not
die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along
these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to
anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of
cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting
apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment
strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely
in human subjects.. It is used,
in contrast to necrosis, to describe the situation in
which a cell actively pursues a course toward death
upon receiving certain stimule
A detailed description of programmed cell death mechanism also called Apoptosis.
It explains about the factors, mechanism and pathways involved in the apoptosis.
Cell death, particularly apoptosis, is probably one of the
most widely-studied subjects among cell biologists.
Understanding apoptosis in disease conditions is very
important as it not only gives insights into the pathogenesis
of a disease but may also leaves clues on how
the disease can be treated. In cancer, there is a loss of
balance between cell division and cell death and cells
that should have died did not receive the signals to do
so. The problem can arise in any one step along the way
of apoptosis.Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions.
It is also one of the most studied topics among cell biologists. An understanding of the underlying mechanism of
apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some, the problem is due
to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the
culprit. Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not
die. The mechanism of apoptosis is complex and involves many pathways. Defects can occur at any point along
these pathways, leading to malignant transformation of the affected cells, tumour metastasis and resistance to
anticancer drugs. Despite being the cause of problem, apoptosis plays an important role in the treatment of
cancer as it is a popular target of many treatment strategies. The abundance of literature suggests that targeting
apoptosis in cancer is feasible. However, many troubling questions arise with the use of new drugs or treatment
strategies that are designed to enhance apoptosis and critical tests must be passed before they can be used safely
in human subjects.. It is used,
in contrast to necrosis, to describe the situation in
which a cell actively pursues a course toward death
upon receiving certain stimule
A detailed description of programmed cell death mechanism also called Apoptosis.
It explains about the factors, mechanism and pathways involved in the apoptosis.
Placebo effect in clinical research is a fascinating and widely researched phenomenon in biomedical research and medicine in general. Presentation is an overview of origins and impact of placebo effect in development of new medicines.
The p53 gene like the Rb gene, is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy
APOPTOSIS & CANCER
How is the initiator caspase frist activated in response to an apoptotic signal?
The role of pRB in controlling transcription of genes
The Role of p53: Guardian of the Genome
Mutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cells to Grow
This presentation is targeted for MBBS, MD and BDS students that describes briefly about aetiopathogenesis, tumour markers, anti cancer agents, apoptosis
Basic Mutagenic signal Transduction or the cancer signal transduction that control cell cycle are important pathways to understand cancer in molecular level and to invent targeted treatment.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
6. Caspases
Cysteine-dependent aspartate specific proteases
Have a cysteine at the active site
Cleave target just after aspartic acid residues
Substrate specificity is determined by the 4 residues upstream of
cleavage site( towards N-terminal)
Exist in cytosol as single chain proenzymes (procaspases) which
are activated when cleaved by other caspases
Once activated, cleave other caspases – results in proteolytic
cascade
Also cleave key proteins in the cell, causing the characteristic
morphology and biochemistry of apoptosis.
7. 3 Types of Caspases
• Inflammatory Caspases: -1, -4, and -5
• Initiator Caspases: -2, -8, -9, -10& -12
– Long N-terminal domain
– Interact with effector caspases
• Effector Caspases: -3, -6, and -7
– Little to no N-terminal domain
– Initiate cell death
14 CASPASES identified in humans.
8.
9.
10.
11. Antiapoptotic
Proapoptotic
Bcl-2 family members
A very large family with 30 members identified and belongs to both:
Bid
Bim
Bik
Bad
Bmf
Hrk
Noxa
Puma
Blk
BNIP3
Spike
BH1, BH2,BH
3,BH4
BH
3
BH1, BH
2,BH3
15. Youle and Strasser (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nature
Reviews Molecular Cell Biology, 9, 47-59
BH3 only protein binding specificity for BCL-2 homologues
BIM and PUMA bind to all BCL-2 family members tested; by contrast
NOXA only binds to A1 and MCL1.
These binding specificities recapitulate the ability of these proteins to
activate apoptosis e.g. BIM et al can induce apoptosis alone whereas
a combination of NOXA and BAD is required.
16.
17.
18. IAPs (Inhibitors of Apoptosis)
These proteins act inhibiting caspase activity in 2 different ways:
• Direct binding inhibiting the proteolytic activity of caspases
• Marking caspases for ubiquitination and so degradation
Inhibited by SMAC/DIABLO.
Salvesen and Duckett Nat rev mol cell biol (2002)
28. Lauber et al.(2004) Fig 2 Lack of “don’t eat me” signals on the
surface of apoptotic cells
29.
30. Anterior chamber of the eye and testes fail to elicit an immune response because
these cells produce lots of FasL, so kill immune cells when they enter these
sites.
Possible therapy by inducing production of FasL in other tissues – lowering
need for immune rejection drugs
ORGAN TRANSPLANTS
39. 1. p53 mediates apoptosis in response to DNA damage, oncogene
expression (adenovirus E1A, myc etc.), or withdrawal of growth
factors
2. Overexpression wild-type of p53 leads to apoptosis
3. p53 induces apoptosis through transcriptional activation of
proapoptotic genes, such as Puma, Noxa, p53AIP1, Bax, Apaf-1 etc.
4. DNA-damage leads to mitochondrial translocation of p53.
4.p53 binds to Bcl-2 family protein Bcl-xL to influence cytochrome c
release.
p53 in apoptosis
40. p53 binds to Bcl-xL and releases Bax
.
Bax is sequestered by
Bcl-xL and inactive
Bax is released by p53
from Bcl-xL and forms
oligomers, leading to
apoptosis
. p53 can release both proapoptotic multidomain proteins
and BH3-only proteins
41. p53 and Puma in
apoptosis
Ref: K.
Vousden, Science,
2005
42. p53 in DNA repair
and apoptosis
Ref: Bensaad &
Vousden, Nature
Med, 2005
ROS: reactive oxygen species
G1- S
43. Role of P53 in DNA damage induced Apoptosis
• DNA damage activate
ATM & Chk2 protein
kinases
• Phosphorylation of P53
• Activate Cdk inhibitor
P21, which inhibits
Cdk2/cyclin E
complexes, halting cell
cycle progression in G1
NOXA
44. The p53-MDM2 feedback loop
1. MDM2 binds to p53 N-terminal transactivation
domain and inhibits p53-dependent transcription.
2. MDM2 is a transcription target of p53.
3. MDM2 is an E3 ubiquitin ligase of p53, thus
targeting p53 for proteolytic degradation.
4. MDM2 knockout is lethal for mouse embryonic
development, but simultaneous deletion of p53
and MDM2 genes rescues MDM2-KO.
46. Ref: Nature 408, 307 - 310 (2000)
Viral oncogenes and the p53 network
47. Genetic Control of "Genetically
Programmed Cell Death"
Cellular Location of
Protein Product
Mitochondrial Membrane
Nuclear Envelope
Endoplasmic Reticulum
Nucleus
Nucleus
Cell Membrane
Effect on Apoptosis
Blocks
Stimulates
Wild-type Stimulates
Mutant Blocks
Stimulates
ApoGenes
bcl-2
myc
p53
p53*
APO-1/
FAS
Apoptosis
Gene
48. Tumor-derived mutations affecting
apoptosis
Protein Role in apoptosis Ref
ATM Mutated in ataxia-talangiectasia syndrome. Senses DNA
double strand breaks and stabilizes p53. Deficiencies
increase risk of developing haematological malignancies
and breast cancer
Khanna and
Jackson, 2001
Bax (p53 target
gene)
Mutated or decreased expression in some tumors.
Mediates mitochondrial membrane damage. Sufficient
but not necessary for drug-induced apoptosis.
Rampino et al.,
1997
Bak Mutated or decreased expression in some tumors.
Mediates mitochondrial membrane damage. Sufficient
but not necessary for drug-induced apoptosis.
Kondo et al., 2000
PTEN (p53
target gene)
Mutated or altered expression in cancers. Regulates Akt
activation and subsequent phosphorylation of Bad. Loss
of PTEN results in resistance to many apoptotic stimuli.
Di Cristofano and
Pandolfi, 2000
Ref: Cell, 2002, 108:153-164
49. Tumor-derived mutations affecting
apoptosis
Protein Role in apoptosis Ref
Apaf-1 (p53
target gene)
Mutated and transcriptionally silenced in melanoma
and leukemia cell lines. Necessary for activation of
caspase-9 following cytochrome c release. Apaf-1-/-
cells are chemoresistant.
Soengas et al., 2001
CD-95/Fas Mutated and down-regulated in lymphoid and solid
tumors. Initiates the extrinsic apoptotic pathway. Loss
of function is associated with resistance to drug-
induced cell death.
Muschen et al., 2000
TRAIL-
R1/R2
Mutated in metastatic breast cancers. Initiate the
extrinsic apoptotic pathway. Mutations lead to
suppression of death receptor-mediated apoptosis.
Shin et al., 2001
Caspase-8 Gene silenced in neuroblastomas. Activates both
extrinsic and intrinsic apoptotic pathways. Silencing
results in resistance to drug-induced apoptosis.
Teitz et al., 2000
Ref: Cell, 2002, 108:153-164
50. Tumor-derived mutations affecting
apoptosis
Protein Role in apoptosis Ref
Bcl2 Frequently overexpressed in many tumors. Antagonises
Bax and/or Bak and inhibits mitochondrial membrane
disruption. Inhibits drug-induced apoptosis.
Reed, 1999
MDM2 Overexpressed in some tumors. Negative regulator of
p53. Inhibits drug-induced p53 activation.
Sherr and Weber,
2000
IAPs Frequently overexpressed in cancer. Down regulation
of XIAP induces apoptosis in chemoresistant tumors.
Deveraux and Reed,
1999
NF B Deregulated activity in many cancers. Transcriptionally
activates expression of anti-apoptotic members of the
Bcl-2 and IAP families. Can inhibit both the extrinsic
and intrinsic death pathways and induce drug-
resistance.
Baldwin, 2001
Ref: Cell, 2002, 108:153-164
51. Tumor-derived mutations affecting
apoptosis
Protein Role in apoptosis Ref
p53 Mutated or altered expression in many cancers.
Initiates the intrinsic apoptotic pathway. p53-/-
cells are resistant to drug induced apoptosis.
Vogelstein et al., 2000
p19ARF Mutated or altered expression in many cancers.
Blocks MDM2 inhibition of p53. Enhances drug-
induced apoptosis by p53.
Sherr and Weber, 2000
Rb Mutated in some cancers, and functionally
disrupted in many cancers. Inhibits E2F-
medidated transcription. Loss of Rb function
induces p53-dependent and independent apoptosis.
Harbour and Dean,
2000
Chk2 Mutated in Li-Fraumeni syndrome. Senses DNA
double strand breaks and phosphorylates and
stabilizes p53.
Khanna and Jackson,
2001
Ref: Cell, 2002, 108:153-164
52. Tumor-derived mutations affecting
apoptosis
Protein Role in apoptosis Ref
Myc Deregulated expression in many cancers. Induces
proliferation in the presence of survival factors, such as
Bcl-2, and apoptosis in the absence of survival factors.
Can sensitise cells to drug-induced apoptosis.
Evan and Vousden,
2001
Akt Frequently amplified in solid tumors. Phosphorylates
Bad. Hyperactivation induces resistance to a range of
apoptotic stimuli including drugs.
Datta et al., 1999
PI3K Overexpressed or deregulated in some cancers.
Responsible for activation of Akt and downstream
phosphorylation of Bad. Inhibition of PI3K enhances
chemotherapeutic drug-induced apoptosis.
Roymans and
Slegers, 2001
Ras Mutated or deregulated in many cancers. Activates PI3K
and downstream pathways. Induces proliferation and
inhibits c-myc and drug-induced apoptosis.
el-Deiry, 1997
Ref: Cell, 2002, 108:153-164
53. Tumor-derived mutations affecting
apoptosis
Protein Role in apoptosis Ref
FLIP Overexpressed in some cancers. Prevents activation of
caspase-8 and apoptosis induced by some
chemotherapeutic drugs.
Tepper and Seldin,
1999
Ref: Cell, 2002, 108:153-164
54. Tumor advantages following p53
mutations
1. Cell cycle - mutant cells are able to progress
through the cell cycle and divide, passing on
mutations.
2. Apoptosis - these cells ignore signals to commit
cell suicide.
3. Genetic instability - continued division without
checkpoints leads to chromosomal
aberrations, incorrect rejoining of chromosomes
activation of oncogenes and inactivation of tumor
suppressor proteins
55. Therapeutic applications of
regulating apoptosis
Promote apoptosis in
cancer cells:
Lymphoma/leukemia
Oral cancer
Brain tumors
Prostate
Colon
etc.
Prevent apoptosis in
certain disorders and
degenerative diseases:
AIDS
Ischemia
Alzheimer's/Parkinson's
etc.
56. Apoptosis in the treatment of cancer
An important goal of cancer drug development should be to
facilitate apoptosis in neoplastic cells. Drugs that restore apoptosis
might selectively kill cancer cells that have triggered a death signal
and have become dependent on the deregulation of apoptosis
pathways.
Strategies already used:
• Administration of death ligand
• Bcl-2 family inhibitors
• XIAP inhibitors
Fesik Nat Rev Cancer (2005)
57.
58. Ribozyme Inhibition of Bcl-2 Expression
• Apoptosis removes damaged cells from the body. The
bcl-2 gene prevents this.
• The role of bcl-2 in oral cancer and glioblastoma is
unexplored.
• We constructed a hammerhead ribozyme that would
digest the bcl-2 mRNA message and delivered it to oral
cancer and glioblastoma cells with an adenovirus
vector.
62. APOPTOSIS: Role in Disease
AGING
Aging --> both too much and too little apoptosis
(evidence for both)
Too much (accumulated oxidative damage?)
---> tissue degeneration
Too little (defective sensors, signals?
---> dysfunctional cells accumulate
hyperplasia (precancerous lesions)
63.
64.
65. „Don't think of death as an ending. Think of it as a really effective way of
cutting down your expenses.” Woody Allen
Editor's Notes
Caspases cleave keratin 18 at two sites during apoptosis. Cleavage at Asp396 generates a neo-epitope recognized by the monoclonal antibody M30.[6] This antibody does not recognize uncleaved K18 and is therefore specific for apoptotic epithelial cells. M30 Apoptosense ELISA utilizes a second monoclonal antibody (M5) which recognizes an epitope N-terminal from the M30 epitope.