Rucete ✏ Lehninger Principles of Biochemistry In a Nutshell
12.9 Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death
This chapter explains how cancer develops through failures in cell-cycle control, mutations in oncogenes, tumor suppressor genes, and DNA-repair genes, and how apoptosis protects the body by eliminating dangerous or unnecessary cells. Cancer usually results from multiple accumulated genetic changes rather than a single mutation.
Normal Balance of Cell Production and Cell Loss
• Tumors and cancer result from uncontrolled cell division.
• Under normal conditions, extracellular growth factors regulate resting cells and stimulate division when needed.
• Some growth factors also promote differentiation.
• Healthy tissues maintain a balance between formation of new cells and destruction of old cells.
• This balance is a form of organismal homeostasis.
Examples of Normal Cell Turnover
• Skin cells are replaced every few weeks.
• White blood cells are replaced every few days.
• Continuous renewal depends on accurate regulation of proliferation.
How Tumors Form
• When regulatory proteins are defective, cells may divide repeatedly without control.
• A clone of abnormal cells can accumulate.
• This expanding mass is called a tumor.
• When tumor growth interferes with normal tissues or spreads aggressively, cancer develops.
Main Cause of Cancer
• The direct cause is usually a genetic defect in one or more proteins that regulate cell division.
• Mutations may be inherited from a parent.
• Mutations may also arise in somatic cells.
• Environmental mutagens, carcinogens, or radiation can damage DNA and create mutations.
• In many cancers, both inherited and environmental factors contribute.
• Usually more than one mutation is required for fully unregulated growth.
Oncogenes: Mutant Growth-Promoting Genes
• Oncogenes are mutated forms of genes encoding signaling proteins involved in cell-cycle regulation.
• They were first discovered in tumor-causing viruses.
• Later it was found that these viral genes came from normal host genes called proto-oncogenes.
• Proto-oncogenes normally encode proteins that regulate growth.
How Viral Oncogenes Arise
• During infection, host DNA containing a proto-oncogene may be copied into a viral genome.
• Viral genomes replicate rapidly and accumulate mutations because viral systems often lack strong DNA proofreading or repair.
• The copied proto-oncogene can become truncated or mutated.
• This altered gene becomes an oncogene.
• If the virus infects another host cell, the oncogene may integrate into host DNA and disrupt normal division control.
Nonviral Formation of Oncogenes
• Carcinogens can damage DNA in a normal tissue cell.
• If a growth-regulating gene is altered, the effect may mimic a viral oncogene.
• The result is failed control of division.
Oncogenes Are Genetically Dominant
• A mutation in only one copy of the gene can be enough to drive abnormal growth.
• If one chromosome carries the defective growth-promoting signal, tumor formation may begin.
Types of Proteins Encoded by Oncogenes
• Secreted signaling molecules (growth factors)
• Transmembrane receptors
• Cytoplasmic signaling proteins such as G proteins
• Protein kinases
• Nuclear transcription factors such as Jun and Fos
Constitutively Active Receptors
• Some oncogenes encode receptors with unregulated Tyr kinase activity.
• These receptors signal continued division even without growth factor binding.
• Persistent signaling can cause tumors.
Protein Kinases as Major Cancer Targets
• Many tumors involve mutations in signaling kinases.
• Kinases transfer phosphate from ATP to downstream proteins.
• Because abnormal kinases drive cancer growth, kinase inhibitors are important anticancer drugs.
Challenge of Kinase Inhibitors
• Many kinase ATP-binding sites are structurally similar.
• Drugs blocking one kinase may also inhibit essential normal kinases.
• This can produce serious side effects.
• Therefore selectivity is a major goal in drug design.
Examples of Targeted Cancer Therapy
• Imatinib inhibits Abl kinase and is highly effective in chronic myeloid leukemia.
• Erlotinib targets EGFR and is used in certain non-small-cell lung cancers.
• Sunitinib and sorafenib inhibit multiple kinases including VEGFR-related pathways.
• Trastuzumab targets HER2/ErbB2.
• Cetuximab targets EGFR.
• Bevacizumab targets VEGF signaling involved in angiogenesis.
Natural and Experimental Inhibitors
• Some kinase inhibitors come from natural products.
• Others are made synthetically.
• Indirubin inhibits CDK2 and CDK5.
• Roscovitine is a selective CDK inhibitor.
• Many more compounds remain under investigation.
Tumor Suppressor Genes
• Tumor suppressor genes encode proteins that normally restrain cell division.
• Their products act like brakes on proliferation.
• Mutation of these genes can permit tumor growth.
Tumor Suppressor Mutations Are Recessive
• Usually both gene copies must be defective for loss of control.
• If one copy remains normal, enough inhibitory protein may still be produced.
• Therefore tumor suppressor defects are genetically recessive at the cellular level.
Inherited Risk
• A person inheriting one defective copy already has the first mutation in every cell.
• If a somatic mutation later damages the remaining normal copy in one cell, that cell can become cancerous.
Key Tumor Suppressor Examples
• pRb
• p53
• p21
• APC
• DCC
• PTEN-related pathways
Retinoblastoma
• Retinoblastoma is a childhood eye tumor that can cause blindness if untreated.
• Tumor cells contain two defective Rb alleles.
• Children inheriting one mutant Rb copy often develop multiple tumors in both eyes because only one additional mutation is needed in retinal cells.
• A fetus with two mutant Rb alleles in every cell is nonviable.
• Survivors have increased later risk of lung, prostate, and breast cancers.
Sporadic Retinoblastoma
• Children born with two normal Rb alleles can still develop retinoblastoma if both copies mutate in the same retinal cell.
• This is rarer and often causes a single tumor in one eye.
• After about age 3, retinal cells stop dividing, so later cases are uncommon.
Stability Genes (Caretaker Genes)
• Stability genes encode proteins that repair DNA damage.
• They correct errors caused by replication mistakes, radiation, or carcinogens.
• Mutation of these genes increases mutation rates in many other genes.
• This indirectly promotes cancer.
Examples of Stability Genes
• ATM
• XP gene family (xeroderma pigmentosum)
• BRCA1-associated repair pathways
p53 as a Central Guardian
• Mutations in p53 are extremely common in human cancers.
• More than 90% of cutaneous squamous cell carcinomas involve defective p53.
• About 50% of all other human cancers also involve p53 defects.
Li-Fraumeni Syndrome
• Rare individuals inheriting one defective p53 copy develop Li-Fraumeni syndrome.
• They show high rates of early cancers of breast, brain, bone, blood, lung, and skin.
• Additional somatic loss of the second copy leads to multiple tumors.
Three Major Genetic Routes to Cancer
• Oncogenes = accelerator pedal stuck down.
• Tumor suppressor loss = brake failure.
• Stability gene loss = defective repair mechanic allowing damage to accumulate.
Cancer Usually Requires Multiple Mutations
• Most cancers develop gradually over years or decades.
• No single mutation usually explains full malignancy.
• Successive mutations progressively weaken control systems.
Colorectal Cancer as a Multistep Model
• Mutation of both APC copies can create an early adenoma (benign polyp).
• APC defects often produce chromosomal instability.
• Additional mutation in ras commonly converts the lesion into an intermediate adenoma.
• Mutation in DCC often contributes to a late adenoma.
• Loss of both p53 copies can convert the mass into malignant carcinoma.
Seven-Hit Concept in One Pathway
• Two hits in APC
• One activating hit in ras
• Two hits in DCC
• Two hits in p53
• Total = at least seven genetic events in this example pathway.
Why Cancer Risk Increases with Age
• Mutations accumulate over time.
• Therefore the chance of developing metastatic cancer rises with age.
Importance of Early Detection
• If a polyp is detected and removed at the early adenoma stage, later adenomas and carcinomas can often be prevented.
Driver vs Passenger Mutations
• Genome sequencing of many tumors reveals numerous mutations.
• Most are passenger mutations that do not provide growth advantage.
• A smaller subset are driver mutations that directly promote cancer.
• Driver mutations commonly occur in oncogenes and tumor suppressor genes.
Three Functional Categories of Driver Mutations
• Mutations affecting cell survival signaling (Ras, PI3K, MAPK)
• Mutations affecting genome maintenance (ATM, ATR)
• Mutations affecting cell fate decisions such as divide, differentiate, or become quiescent (APC)
Apoptosis: Programmed Cell Death
• Apoptosis is controlled cellular suicide.
• The term means “dropping off,” like leaves falling.
• It allows precise timing of cell death.
When Apoptosis Occurs
• Irreparable DNA damage
• Normal embryonic development
• Tissue shaping
• Immune system quality control
• Menstruation
• Seasonal leaf drop in plants
• Viral infection
• Severe stress such as heat, hyperosmolarity, UV light, or gamma radiation
Developmental Examples
• Cells between developing fingers die so separate digits form.
• During C. elegans development, exactly 131 of 1,090 somatic embryonic cells undergo programmed death.
Immune Tolerance Example
• Antibody-producing cells that react against self molecules can be eliminated by apoptosis in the thymus.
• This helps prevent autoimmune disease.
External Apoptotic Signals
• Apoptosis often begins with an extracellular ligand.
• Tumor necrosis factor (TNF) from immune cells is one example.
• TNF binds specific TNF receptors on the plasma membrane.
Death Domain Signaling
• TNF receptors contain intracellular death domains of about 80 amino acids.
• These domains transmit the suicide signal to cytosolic proteins such as TRADD.
Caspase Cascade
• TRADD signaling activates initiator caspase-8.
• Caspase-8 can activate itself by cleavage of its own proenzyme.
• Caspase cascades amplify the death signal.
Mitochondrial Amplification
• Active caspase-8 targets mitochondria.
• Mitochondria release cytochrome c and effector caspases.
• Cytochrome c binds the proenzyme form of caspase-9.
• This promotes formation of the apoptosome and activates caspase-9.
Execution Phase
• Activated caspase-9 and downstream caspases digest many cellular proteins.
• A caspase-activated DNase fragments DNA.
• The cell is dismantled in an orderly manner.
Why Apoptosis Is Efficient
• Cellular components are broken into reusable monomers such as amino acids and nucleotides.
• Neighboring cells can reuse these materials.
• Harmful cells are removed without wasting resources.
In a Nutshell
Cancer develops when mutations disrupt the balance between signals that promote division, genes that suppress division, and genes that repair DNA damage. Oncogenes act like stuck accelerators, tumor suppressor genes act like failed brakes, and stability gene defects allow further mutations to accumulate. Apoptosis is a protective self-destruction program that removes damaged, infected, or unnecessary cells through TNF receptors, caspases, mitochondrial cytochrome c release, and controlled recycling of cell components.