Molecular Cell Biology
Eighth Edition   ©2016

Molecular Cell Biology

Harvey Lodish (Massachusetts Institute of Technology) , Arnold Berk (University of California, Los Angeles) , Chris A. Kaiser (Massachusetts Institute of Technology) , Monty Krieger (Massachusetts Institute of Technology) , Anthony Bretscher (Cornell University) , Hidde Ploegh (Massachusetts Institute of Technology) , Angelika Amon (Massachusetts Institute of Technology) , Kelsey C. Martin (University of California, Los Angeles)

  • ISBN-10: 1-4641-8339-2; ISBN-13: 978-1-4641-8339-3; Format: Cloth Text

Medical Connections
As always, the new edition highlights advances in basic cellular and molecular biology that led to new treatments for cancer and other significant human diseases. These medical examples are woven throughout the chapters where appropriate to give students an appreciation for the clinical applications of the basic science they are learning.

2. Chemical Foundations
• Stereoisomers of small molecules as drugs—sterically pure molecules have different effects from mixtures 
• Cholesterol is hydrophobic and must be transported by lipoprotein carriers LDL or HDL 
• Essential amino acids must be provided in agricultural feed 
• Saturated, unsaturated, and trans fats, their molecular structures and nutritional consequences 

3. Protein Structure and Function
• Protein misfolding and amyloids in neurodegenerative diseases such as Alzheimer’s and Parkinson’s 
• Small molecules can be used as drugs (aspirin) or in chemical warfare (sarin gas) 
• Small molecule inhibitors of the proteasome are used to treat certain cancers 
• Genetic diseases and pathogens disrupt GTPases, GAPs, GEFs, and GDIs 

4. Culturing and Visualizing Cells
• 3-D printing technology may be used to grow replacement organs 

5. Fundamental Molecular Genetic Mechanisms
• High-resolution structures can help identify small molecule inhibitors of bacterial, but not eukaryotic, ribosomes 
• Mutations in mismatch repair proteins lead to hereditary nonpolyposis colorectal cancer 
• Nucleotide excision repair proteins were identified in xeroderma pigmentosum patients 
• Human viruses HTLV, HIV-1, and HPV initiate infection by binding to specific cell surface molecules, and some integrate their genomes in the host cell’s DNA 

6. Molecular Genetic Techniques
• The sickle cell anemia allele is an example of one that exhibits both dominant and recessive properties, depending on the phenotype being examined 
• DNA microarrays can be useful as medical diagnostic tools 
• Recombinant DNA techniques are used to mass-produce therapeutically useful proteins such as insulin and G-CSF 
• Most genetic diseases are inherited, rather than de novo mutations 
• A CFTR knockout mouse line is useful in studying cystic fibrosis 

7. Biomembrane Structure
• ABO blood types are determined by the carbohydrates attached to glycoproteins on the surface of erythrocytes 
• Atherosclerosis is marked by accumulation of cholesterol, other lipids, and other biological substances in an artery, and is responsible for the majority of deaths due to cardiovascular disease in the US 

8. Genes, Genomics, and Chromosomes
• Microsatellites have a tendency to expand and can cause repeat diseases such as Huntington and myotonic dystrophy 
• L1 transposable elements can cause genetic diseases by inserting into new sites in the genome 
• Exon shuffling can result in bacterial resistance to antibiotics, a growing challenge in hospitals 
• The neurofibromatosis gene NF1 is an example of how bioinformatics techniques can be used to identify the molecular basis of a genetic disease 
• Telomerase is abnormally activated in most cancers 

9. Transcriptional Control of Gene Expression

• TFIIH subunits were first identified based on mutations that cause defects in DNA repair associated with a stalled RNA polymerase 
• HIV encodes the Tat protein, which inhibits termination by RNA polymerase II 

10. Post-transcriptional Gene Control
• Synthetic oligonucleotides are being used in treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy 
• Multiple neurological disorders result from abnormalities in the function of nuclear RNA binding proteins and the expansion of microsatellite regions within transcription units 
• Thalassemia commonly results from mutations in globin-gene splice sites that decrease splicing efficiency but do not prevent association of the pre-mRNA with snRNPs 
• Genes encoding components of the mTORC1 pathway are mutated in many cancers and mTOR inhibitors combined with other therapies may suppress tumor growth 
11. Transmembrane Transport of Ions and Small Molecules
• Aquaporin 2 levels control the rate of water resorption from urine being formed by the kidney 
• Certain cystic fibrosis patients are being treated with a small molecule that allows a mutant protein to traffic normally to the cell surface  
• SGLT2 inhibitors are being tested for treatment of type II diabetes 
• Drugs that inhibit the Na+/K+ ATPase in cardiac muscle cells are used in treating congestive heart failure 
• Oral rehydration therapy is a simple, effective means of treating cholera and other intestinal pathogens 
• Mutations in CIC-7, a chloride ion channel, results in defective bone resorption characteristic of the hereditary bone disease osteopetrosis 

12. Cellular Energetics
• Sensitivity of mitochondrial ribosomes to the aminoglycoside class of antibiotics, including chloramphenicol, can cause toxicity in patients 
• Mutations and large deletions in mtDNA cause certain diseases, such as Leber’s hereditary optic neuropathy and Kearns-Sayre syndrome 
• Cyanide is toxic because it blocks ATP production in mitochondria 
• Reduction in cardiolipin amounts, as well as its abnormal structure, within Barth’s syndrome patients results in heart and skeletal muscle defects and other abnormalities 
• Reactive oxygen species are by-products of electron transport that can damage cells 
• ATP/ADP antiporter activity was first studied over 2000 years ago through the examination of the effects of poisonous herbs 
• There are two related subtypes of thermogenic fat cells 

13. Moving Proteins into Membranes and Organelles
• A hereditary form of emphysema results from misfolding of proteins in the ER 
• Autosomal recessive mutations that cause defective peroxisome assembly can lead to several developmental defects often associated with craniofacial abnormalities, such as those associated with Zellweger syndrome 

14. Vesicular Traffic, Secretion, and Endocytosis
• Certain cases of cystic fibrosis are caused by mutations in the CFTR protein that prevent movement of this chloride channel from the endoplasmic reticulum to the cell surface 
• Study of lysosomal storage diseases reveal key elements of the lysosomal sorting pathway 
• The hereditary disease familial hypercholesterolemia results from a variety of mutations in the LDLR gene 

15. Signal Transduction and G Protein–Coupled Receptors
• Therapeutic drugs using the TNFα-binding domain of TNFα receptor are used to treat arthritis and other inflammatory conditions 
• Monoclonal antibodies that bind HER2 and thereby block signaling by EGF are useful in treating breast tumors that overexpress HER2 
• The agonist isoproterenol binds more strongly to its receptor than epinephrine and is used to treat bronchial asthma, chronic bronchitis, and emphysema 
• Some bacterial toxins (e.g. Bordetella pertussis, Vibrio cholerae, certain strains of E. coli) catalyze a modification of a G protein in intestinal cells, increasing intracellular cAMP, which leads to loss of electrolytes and fluids 
• Nitroglycerin decomposes to NO, a natural signaling molecule, which, when used to treat angina, increases blood flow to the heart 
• PDE inhibitors elevate cGMP in vascular smooth muscle cells and have been developed to treat erectile dysfunction 

16. Signaling Pathways That Control Gene Expression
• Many tumors contain inactivating mutations in either TGF-β receptors or Smad proteins and are resistant to growth inhibition by TGF-β 
• Epo and G-CSF are used to boost red blood cells and neutrophils, respectively, in patients with kidney disease and certain cancer therapies that affect blood cell formation in the bone marrow 
• Many cases of SCID result from a deficiency in the IL-2 receptor gamma chain and can be treated by gene therapy 
• Mutant Ras proteins that bind but cannot hydrolyze GTP, locking Ras in an active GTP-bound site, contribute to oncogenic transformation 
• Potent and selective inhibitors of Raf are being clinically tested with patients with melanomas caused by mutant Raf proteins 
• The deletion of the PTEN gene in multiple types of advanced cancers results in the loss of the PTEN protein, contributing to the uncontrolled growth of cells 
• High levels of free β-catenin, caused by aberrant hyperactive Wnt signaling, is associated with the activation of growth-promoting genes in many cancers  
• Inappropriate activation of Hh signaling associated with primary cilia is the cause of several types of tumors 
• Increased activity in ADAMs can promote cancer development and heart disease 
• The brains of Alzheimer’s patients display the accumulation of amyloid plaques containing aggregates of the Aβ42 peptide 
• Diabetes mellitus is characterized by an impaired regulation of blood glucose, which can lead to major complications if left untreated 

17. Cell Organization and Movement I: Microfilaments
• Hereditary spherocytic anemias can be caused by mutations in spectrin, band 4.1, and ankyrin 
• Duchenne muscular disease affects the protein dystrophin resulting in progressive weakening of skeletal muscle 
• Hypertrophic cardiomyopathies result from different mutations in proteins of the heart contractile machinery 
• Blood tests that measure the level of cardiac-specific troponins are used to determine the severity of a heart attack 

18. Cell Organization and Movement II: Microtubules and Intermediate Filaments 
• Some drugs (e.g. colchicine) bind tubulin dimers and restrain them from polymerizing into microtubules whereas others (e.g. taxol) bind microtubules and prevent depolymerization 
• Defects in LIS1 cause Miller-Dieker lissencephaly disease in early brain development, leading to abnormalities 
• Some diseases, such as ADPKD and Bardet-Biedl syndrome, have been traced to defects in primary cilia and intraflagellar transport 
• Keratin filaments are important to maintaining the structural integrity of epithelial tissues by mechanically reinforcing the connections between cells 
• Mutations in the human gene for lamin A cause a wide variety of diseases termed laminopathies 

19. The Eukaryotic Cell Cycle
• In cohesinopathies, mutations in cohesion subunits or cohesion loading factors disrupt expression of genes critical for development, resulting in limb and craniofacial abnormalities and intellectual disabilities 
• Aneuploidy leads to misregulation of genes and can contribute to cancer development 
• Aneuploid eggs are largely caused by chromosome mis-segregation in meiosis I or nondisjunction, leading to miscarriage or Down syndrome 

20. Integrating Cells Into Tissues
• The protein CDHR3 enables Class C rhinoviruses (RV-C) to bind to airway epithelial cells, enter them, and replicate, causing respiratory diseases including exacerbation of asthma 
• The cadherin desmoglein is the predominant auto-antibody in the skin disease pemiphigus valgaris 
• Some pathogens, such as hepatitis C virus and the enteric bacteria Vibrio cholerae, have evolved to exploit the molecules in tight junctions 
• Mutations in connexin genes cause a variety of diseases 
• Defects in the glomerular basement membrane can lead to renal failure 
• In cells deprived of ascorbate, the pro-α collagen chains are not hydroxylated sufficiently to form the structural support of collagen necessary for healthy blood vessels, tendons, and skin, resulting in scurvy 
• Mutations affecting of type I collagen and its associated proteins cause a variety of diseases, including osteogenesis imperfecta 
• A variety of diseases, often involving skeletal and cardiovascular abnormalities (e.g. Marfan syndrome), result from mutations in the genes encoding the structural proteins of elastic fibers or the proteins that contribute to their proper assembly 
• Connections between the ECM and cytoskeleton are defective in muscular dystrophy 
• Leukocyte-adhesion deficiency is caused by a genetic defect that results in the leukocytes’ inability to fight infection, thereby increasing susceptibility to repeated bacterial infections 

21. Stem Cells, Cell Asymmetry, and Cell Death

• iPS and ES cells are valuable in generating in cell culture models of difficult-to-study diseases, such as ALS; these can be used to screen for potential drug treatments 
• The stem cells in transplanted bone marrow can generate all types of functional blood cells making such transplants useful for patients with certain hereditary blood diseases, as well as cancer patients who have received irradiation or chemotherapy 

22. Cells of the Nervous System
• Channelopathies, including some forms of epilepsy, are caused by mutations in genes that encode ion channels 
• The topical anesthesia lidocaine works by binding to amino acid residues along the voltage gated Na+ channel, locking it in the open but occluded state 
• The cause of MS is not known but seems to involve either the body’s production of auto-antibodies that react with myelin basic protein or the secretion of proteases that destroy myelin proteins 
• Peripheral myelin is a target of autoimmune disease, mainly involving the formation of antibodies against Po 
• The key role of VAMP in neurotransmitter exocytosis can be seen in the mechanism of action of botulinum toxin  
• Neurotransmitter transporters are targets of a variety of drugs of abuse (e.g. cocaine) as well as therapeutic drugs commonly used in psychiatry (e.g Prozac, Zoloft, Paxil) 
• Nicotinic acetylcholine receptors produced in brain neurons are important in learning and memory; loss of these receptors is observed in schizophrenia, epilepsy, drug addiction, and Alzheimer’s disease 
• Studies suggest that the voltage-gated Na+ channel Nav1.7 is a key component in the perception of pain 
• People vary significantly in sense of smell 
• Synaptic translation of localized mRNAs is critical to the formation and the experience-dependent plasticity of neural circuits, and alterations in this process result in neurodevelopmental and cognitive disorders 

23. Immunology
• The immunosuppressant drug cyclosporine inhibits calcineurin activity through the formation of a cyclosporine-cyclophilin complex, thus enabling successful allogenic tissue transplantation 
• Vaccines elicit protective immunity against a variety of pathogens 
• Increased understanding of the molecular cell biology of tumors is revolutionizing the way cancers are diagnosed and treated