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Module 4 Class 2 Online

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Module 4 Class 2 Online

Uploaded by

shalinim8387
Copyright
© © All Rights Reserved
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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About Apoptosis

Apoptosis
Plasma membrane blebs

Cell shrinkage

Nucleus condensation (pyknosis)

Endonucleases: degrade
chromosome, ~170 bp

Nucleus fragmentation

Engulfed by phagocytes
Apoptosis: death for survival
Cell termination, homeostasis, development
etc

DNA damage

p53: cell cycle arrest


DNA repair vs. apoptosis

Caspases: Cysteine protease cascade

vs. blood coagulation


Apoptosis pathways
Apoptosis pathway - extrinsic

TNF (tumor necrosis factor): cytokine


TNF receptor

TRADD (TNFR-associated DD)


FADD (Fas-associated DD)

DD: death domain

Caspase 8

Caspase cascade

Apoptosis
Death receptor and mitochondrial apoptotic pathways
DISC (8) - extrinsic
Extracellular

Intracellular endonucleases

apoptosis

Apoptosome (9) - Intrinsic


Mitochondrial apoptotic pathway : intrinsic

Mitochondria: aspiration

Pore: cytochrome c release

Pore forming: Bax, Bak


Pore facilitator: Bad, Bid
Anti-pore: Bcl-2

Apoptosome
Cytochrome c
Apaf-1
Pro-caspase 9

Caspase 9

Apoptosis
Cancer Biology
Oncogenesis : More than one event

Oncogenesis involves multiple events


(e.g., p53 mutation + abnormal proliferation with Ras mutation)
Carcinogenesis : Stages of
Stage 0
cancer
Creation of cancer cells

Stage I
Restricted to one part
of the body

Stage II
Locally advanced

Stage III
Locally advanced

Stage IV
Often metastasized, or
spread to other organs or
throughout the body.

Sequential mutations
involved and required
ransformation : causes
 Point Mutation
APC gene -
adenomatous polyposis
coli (APC) gene is a
key tumor suppressor
gene.

DCC gene - Deleted in


Colorectal Carcinoma (
dependence receptor)

KRAS - oncogene
Transformation : causes
The proto-oncogene c-MYC

1.Translocation
2.Deletion
3.Insertion
 Burkitt's lymphoma is most common in children living
in sub-Saharan Africa, where it's related to the Epstein-
Barr virus (EBV) and chronic malaria.
Transformation : causes

1.Translocation
2.Deletion
3.Insertion
Transformation : causes
This causes Myc to be
constitutively expressed.

1.Translocation
2.Deletion
3.Insertion

By Avian Leukosis virus (ALV)


Metastasis

Spreading of cancer cells throughout


the body.

An environment where tumor cells can


proliferate, invade surrounding tissues,
be released into the circulation, invade
a distant organ, establish their own
blood supply (angiogenesis), and grow.

Each of these steps as drug targets


Metastasis
UPA
(Urokinase plasminogen activator)

Plasminogen - plasmin

Procollagenases

Collagenases

Extracellular matrix breakdown

Secreted proteases and metastasis


Cancer and angiogenesis

VEGF
(vascular endothelial cell
growth factor)

FGF
(fibroblast growth factor)

Blood vessel induction


into tumor mass

Nutrition and oxygen


supply
Cancer and angiogenesis
Oncogene pathways

Tumor suppressor pathways


Protooncogene products that regulate cell division
and apoptosis

Activators of cell division

Growth factors PDGF, FGF, etc


Growth factor receptors PDGFR, EGFR, etc
Tyrosine kinase (cytoplasmic) Src
Adaptor proteins Grb-2
Ras GTP-binding proteins K-Ras, H-Ras, N-Ras
Kinases and kinase cofactors Cyclins, CDK, CAK, MAPKs
Phosphatases CDC25
Transcription factors Myc, Jun, Fos, E2F

Activators of apoptotic resistance (survival)

Bcl-2, Bcl-XL
MDM2
XIAP
Akt and Raf (MAPKKK)
NFkB (transcription factor)
How can virus induce cancer?
Cervical cancer induced by HPV

Human Papillomavirus Virus: DNA virus


Skin, mucous membrane

Benign skin warts, genital warts


~50% women infected
Cervical cancer: 10,000 women (4,000 death)
HPV induces uncontrolled proliferation: how?

E6 – inactivates p53
E7 – inactivates pRB2
Cancer treatment

Normal vs. cancer cells


Proliferation

Chemotherapy
DNA mutagens

Radiation therapy
X-ray, ionizing radiations

Drug
Velcade, Herceptin
Proteasome as a drug target
Velcade: Bortezomib

The first drug targeting


proteasome

Anti-cancer (multiple myeloma


and some lymphoma)

Cancer cell survival requires


proteasomal degradation of
proteins

Partially inhibits proteasome,


affecting a broad range of
signaling Pathways
P53-MDM2 inhibitor nutlin-2

Synthesis of E3 inhibitor

Nutlin-2 binds to p53 pocket,


inhibiting MDM2 binding.

How about targeting other


~500 E3s?
Monoclonal Ab treatment - Herceptin (Trastuzumab)

Monoclonal antibody to HER2


Women with breast cancer
Prevents proliferation
Epidermal growth factor receptor-2 (HER2)

Constitutively active mutant


by dimerization

Ras
MAPK
c-Jun
Cyclin
CDK
Rb
E2F
G1S progression
Intermediate signaling
molecule Target –
Flavopiridol Blocks binding of ATP
Growth factor receptor target
Glevec & Tarceva
Host Pathogen
Interaction
Mod 4
Shomu’s biology
Book used- Brock Biology of Microorganisms
Species Interactions
PATHOGENICITY vs. VIRULENCE

PATHOGENICITY – the ability to cause disease

VIRULENCE – The degree of pathogenicity


TRUE PATHOGEN
OPPORTUNISTIC PATHOGEN
INFECTION vs. DISEASE
INFECTION: the colonization and/or
invasion and multiplication of
pathogenic microrganisms in the host
with or without the manifestation of
disease

DISEASE: an abnormal condition of


body function(s) or structure that is
considered to be harmful to the affected
individual (host); any deviation from or
interruption of the normal structure or
function of any part, organ, or system
of the body
EPIDEMIOLOGY
ENDEMIC – Malaria in Africa
EPIDEMIC- SARS, cholera
PANDEMIC – HIV/AIDS
Part 1: ACQUIRING INFECTIOUS AGENTS
PORTAL OF ENTRY/EXIT
INGESTION
INHALATION
DIRECT PENETRATION
Trauma or Surgical Procedure
Needlestick
Arthropod Bite
Sexual Transmission
Transplacental
COLONIZATION: the successful occupation of a new habitat by a species
not normally found in this niche
Adherence (attachment)
INVASION
MULTIPLICATION
Step 1
Step 2 : Adherence and colonization
Step 2 : Mechanism of adherence
Step 2 : Mechanism of adherence
Step 3 : Invasion to the host tissue
Step 3 : Invasion to the host tissue : Virulence factors
INVASIVE FACTORS (invasins): enable a pathogenic microorganism to enter and spread throughout the
tissues of the host body; specific recognition of receptor sites on target cells enhances pathogenic advantage

DEGRADATIVE ENZYMES: a class of protein capable of catalytic reactions; bacterial and host enzymes
both play roles in the disease process

TOXIGENICITY: the ability of a


microorganism to cause disease as
determined by the toxin it produces
which partly determines its virulence
Step 4 : Growth and
division of bacteria in
Host Tissue
Step 4 : Invasion to the host tissue : Virulence factors 2
TOXIGENICITY: the ability of a microorganism to cause disease as determined by the toxin it
produces which partly determines its virulence

1. ENDOTOXIN: a complex bacterial toxin that is composed of protein, lipid, and


polysaccharide (LPS) which is released only upon lysis of the cell

2. EXOTOXINS: a potent toxic substance formed


and secreted by species of certain bacteria
Step 5: MICROBIAL PATHOGENICITY (cont.)
DAMAGE TO HOST
DIRECT DAMAGE
(Tissue Damage from Disease Process):
Toxins
Enzymes

INDIRECT DAMAGE
(Tissue Reactions from Immunopathological Response):
Damage Resulting from Vigorous Host Immune Response (a.k.a,
immunopathogenesis; autoimmune hypersensitivy)
Hypersensitivity Reactions (Types I - IV)
BASIC EFFECTS of ENDOTOXIN
FEVER:
LEUKOCYTOSIS:
METABOLIC EFFECTS :
CELLULAR DEATH:

SEPTIC SHOCK:
DISSEMINATED INTRAVASCULAR
COAGULATION (DIC):
lead to multiple organ damage
ORGAN NECROSIS:
Due to injury
Effects of LPS
Septic shock is a serious medical
condition that occurs when sepsis,
which is organ injury or damage
in response to infection, leads to
dangerously low blood pressure
and abnormalities in cellular
metabolism.

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