Lecture 19Homework Review

Apoptosis and Cancer

Next Two Lectures:Cell-Cell Interactions/Tissues

Early Development and Stem Cells

For Exam III- You are not responsible for any material in assigned chapters relating to Plants!

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Apoptosis:Regulated Cell Death

Role in Killing of Unneeded, Damaged, or Potentially Deleterious Cells

Occurs in Embryonic and Adult Tissues

Proteins Involved are Always Present in Cells- Needs to Be Activated by Stimuli

Can Result From:

Developmental Cues

Withdrawl of Essential Growth Factors

DNA Damage

Various Cell Stresses

Programmed Cell Death

• Cell Death Occurring at a Defined Point in Development

• Usually proceeds by Apoptosis

Mouse Paws

Not All Cell Death is Apoptotic

Apoptosis:

An Active Regulated Process

DNA FragmentationChromatin Condensation

Fragmentation of NucleusCell Shrinks

Formation of Membrane Enclosed Fragments called Apoptotic Bodies

Recognition and Engulfment by Phagocytic Cells

or Neighboring Cells

Oncosis and Necrosis:

Unregulated Cell Death Due to Injury

Cell Swells (Oncosis)

Nucleus Swells

Disruption of Organelles and Rupture/Release of Contents

Contents Released into Extracellular Space

The Morphological Changes of Apoptosis Are Orchestrated by Caspases

Cysteine Proteases that cleave at Aspartic Acid Residues

Activate Apoptosis by Cleaving Specific SubstratesPresent but inactive in cells

Two Main Types of Caspases:

1) Initiators- Need to dimerize to become active “induced proximity”

2) Executioner (Effector) - Need to be proteolytically cleaved to become active- Cleavage is usually Mediated by Initiator Caspases

Zymogens

Once Executioners are Activated their Key Targets of Proteolysis Include:

1)An Inhibitor of a DNAse-Leads to Fragmentation of DNA

2)Nuclear Lamins- Leads to Fragmentation of Nucleus

3)Other Cytoskeletal Associated Proteins- Leads to Disruption of Cytoskeleton and Cell Fragmentation

4)Additional Caspases

Caspase Activation Amplification Cascade

Main Pathways Regulating Caspase Activation During Apoptosis

Intrinsic Pathway- Mitochondrial MediatedMajor Pathway in Mammalian Cells – Outer Mitochondrial Membrane Permeabilization (MOMP)– Release of Cytochrome C from Mitochondrial Intermembrane

Space into Cytosol– Apoptosome Formation- Activation of Initiator Caspase – Effector Caspases Activated

Extrinsic Pathway- Signaling through Death Receptors– Ligand Bound Death Receptors– Adaptor Protein Association– Initiator Caspase Recruitment and Activation– Effector Caspases Activated

Intrinsic Pathway of Apoptosis Activation

Association of Adaptor with Procaspase allows

Procaspase self cleavage

MOMPs

cytochrome c Release

Apoptosome Formation: Adaptor (Apaf1), dATP

cytochrome c and procaspase complex

Active Initiator CaspaseCleaves Effector

Caspases Which now Cleave

Targets

Critical Regulators of Cell Death

Bcl-2 Family – Regulate whether MOMPs Occurs

Anti-Apoptotic Factors - Death Inhibitors

A) Function to Inhibit MOMPs by Pro Apoptotic Factors

Pro-Apoptotic Factors- Death Activators A) Bind and inhibit Death Inhibitors

B) Directly cause Permeabilization of MOM to Stimulate Release of Cytochrome C ( BAX AND BAK)

IAP Family (Inhibitor of Apoptosis)Bind Procaspases prevent activation

Bind Caspases and inhibit Activity

Survival Factor Signaling is Required to Prevent Apoptosis

Programmed Cell Death

in Neuronal Development

Survival Factors Signaling Can Function to

Keep Anti-Apoptotic Factor Bcl-2 Active

No Survival SignalBcl-2 Complexes with BadCan’t preventBAK and BAX MediatedMOMPs

Extrinsic Pathway of Apoptosis Activation:Signaling through the Death Receptors

Ligand Bound Death Receptors

Adaptor Protein and Procaspase Recruitment

Initiator Caspase Activation

Effector Caspases Activated

Target cells :

Viral Infected Cells or Cancer Cells

Removal of Excess Lymphocytes afterInfection

Cancer

Cancer is a Disease of Cells that Proliferate at Inappropriate Times and Locations in the Body.

Tumors (Neoplasms) - Masses of cells derived from a single abnormally proliferating cell. Tumors are Clonal

1. Benign- Noninvasive, Do not affect other tissues

2. Malignant- Cancerous, Locally Invasive and May Spread

Tumors are classified by cell type from which they arise.1. Carcinoma- 90% of human cancers- Malignacy of Epithelial Cells2. Sarcomas – Rare, Solid tumors of connective tissue, such as bone, muscle,

cartilage, and fibrous tissue.3. Leukemias and Lymphomas- 7% of cancers, Blood forming cells and cells of immune system4. Neuroectodermal- Cells of central or peripheral nervous system

The Development of Cancer is a Multistep Process

Typically requires four to six different mutations

Tumorigenesis Occurs by Clonal Expansion:

Yields Population of CellsMore Abnormal and

More AdaptedProliferate, Survive,

Invade and Metastasize

Intravasation: Malignant cells gain access to blood vessels and lymphatic

system and spread

Metastasis: Malignant cells

Establish in distant organs

Initial Cell Proliferating Abnormally

Key Characteristic Normal Cell Cancer Cell

Contact Inhibition of Growth Present Absent

Growth Factor Requirements High Low

Anchorage Dependence Present Absent

Cell Cycle Checkpoints Intact Absent

Karyotypic Profile Normal Abnormal

Proliferative Life Span Finite Indefinite

Cancer cells are also:

Defective in Differentiation

Fail to Undergo Apoptosis

Cancer Cells are Characterized by Several Distinct Properties when Grown in vitro

Cancer Cells Are Created when Certain Genes are Mutated

Mutations can be Inherited, Introduced by Viruses, or Result of DNA Damage (exposure to a mutagen)

1. Oncogenes - Gene whose presence can trigger inappropriate cell proliferation.

Example: ras, bcl-2(Normal version of gene: Proto-oncogene)

2. Tumor Suppressors- Gene whose absence or inactivation can lead to cancer

Usually Function to Block Cell Cycle ProgressionExample: p53, Rb

DNA Repair Genes- Increase Rate of Mutation, provide opportunity for mutation in growth controlling genes, increase rate of tumor progression

Cancer Cells Are Created When Certain Genes are Mutated

Activation of OncogeneCan Also Occur

By:

Overexpression of Proto-oncogene

Translocations that create

hybrid proteinsInhibition of Tumor Suppressor Genes

Oncogenes are Found in Mitogen andGrowth Factor Signal Transduction Pathways

Mutation of Proto-oncogene- Constitutively Active DownstreamSignal Transduction Pathway

Inactivation of Tumor Suppressor Rb

Common Target for Viruses that Cause Tumors (along with p53)

Cancer Cells Exhibit Unlimited Proliferative Ability

Cancer cells avoid senescence by inactivating tumor suppressor genes, p53 and Rb.

Cancer Cells will continue to divide for a period of time

Crisis Point – Large number of Cancer Cells Die- Result of catastrophic rearrangements- due to lack of telomerase

Rare Occasion A Cell Survives- It is Immortalized.At some point- derepressed telomerase expression

~ 90% of cancer cells express significant levels of telomerase