1.

01-B
The Cell as a Unit of Health and Disease
Grig Misiona, MD

D Binding sites for higher order

OUTLINE chromatin structures
RNA transcriptions that are never
I. The Genome translated into proteins but serve in
a.) Non-coding DNA gene regulation
Noncoding regulatory RNAs
b.) Micro-RNA and Long Non-Coding RNA e.g. microRNAs and long noncoding
c.) Plasma Membrane: Protection and Nutrient Acquisition RNAs
II. Cellular Housekeeping Transposons or jumping genes;
a.) Cytoskeleton and Cell-Cell Interactions Mobile genetic elements implicated in gene regulation and
b.) Biosynthetic Machinery: ER and Golgi chromatin organization 
c.) Waste Disposal: Lysosomes and Proteasomes e.g. Telomere (chromosome ends)
III. Cellular Metabolism and Mitochondrial Function Special structural DNA regions Centromere (chromosome tethers) 
IV. Cellular Activation
a.) Cell Signaling  Most common types of DNA variations:
b.) Classification of Extracellular Signaling (Based on Distance 1. Single nucleotide polymorphisms (SNPs)
of Signal Function) o Variants at single nucleotide positions that are almost
c.) Classification of Extracellular Signaling (Based on Location) always biallelic
V. Signal Transduction Pathways o May have a direct influence on disease susceptibility or may
a.) Classification of Receptors (Based on Signaling be “neutral” variant that exerts no effect and may only serve
Mechanisms Used) as marker for linkage disequilibrium
o Effect on disease is weak but may be used to develop
b.) Modular Signaling Proteins, HUBs, and Nodes
effective strategies for disease prevention
VI. Growth Factors and Receptors
a.) Epidermal Growth Factor and Transforming Growth Factor-α
b.) Hepatocye Growth Factor 2. Copy number variations (CNVs)
c.) Platelet-Derived Growth Factor o Made of different numbers of large contiguous stretches of
d.) Vascular Endothelial Growth Factor DNA base pairs
e.) Fibroblast Growth Factor o Often (50%) involves gene-coding sequences; thus, may
f.) Transforming Growth Factor-β underlie a large portion of phenotypic diversity
VII. Interaction with the Extracellular Matrix
a.) Key Functions of the ECM However, these variations in DNA sequences cannot solely
explain phenotypic variations in the human population. These
b.) 2 Basic Forms
“missing link” is now associated with epigenetics (heritable
c.) Key Components of the ECM changes in gene expression that are not caused by alterations in
VIII. Maintaining Cell Population DNA sequence).
a.) Proliferation and the Cell Cycle
b.) Stem Cells HISTONE ORGANIZATION
c.) Regenerative Medicine
Table 2.
THE GENOME Epigenetic Factors that Dictate Cell-Type Specific Differences
in DNA Transcription and Translation to Render Lineage-
specific Programs of Gene Expression.
EPIGENETIC
FACTORS DETAILS

 Chromatin remodeling complexes

 Repositions nucleosomes on DNAe
regulatory elements

 Chromatin “writer” complexes

 Carry out histone modifications
known as “marks” such as
methylaton, acetylation or
phosphorylation
Histones and Histone  e.g. Euchromatin have histone
Modifying Factors marks that make it accessible to
Figure 1. The organization of nuclear DNA RNA polymerases for active
transcription and the reverse is true
for heterochromatin
Centromeres
 Locus for the formation of a kinetochore protein that regulates  “Chromatin erasers”
chromosome segregation at metaphase o Can reverse histone marks

Nucleosome  Chromatin readers

 DNA wound around octameric histone cores o Regulate gene expression by
binding histones that bear particular
marks
NON-CODING DNA
 Connected via DNA linkers In lysine and aginine residues
 Provides the “architectural planning” of an organism  Methylation of lysine residues in
Histone Methylation histone either activates or represses
 Involved in regulating gene expression, often in a cell-type
transcription depending on the
specific fashion. “marked” histone residue. 
 Location of most genetic variations/ polymorphisms associated
to diseases. Thus, gene regulation is said to be important in In lysine residues
disease causation than structural changes in specific proteins  Acetylated by HAT (histone acetyl
Histone Acetylation transferases) which teand to open up
Table 1. the chromatin and increase
Nonprotein Coding Sequences transcription 

Classes of Functional Non- Histone  In serine residues

Protein Coding Sequences Details Phosphorylation  May open up or code sense DNA

Promoter and enhancer Provide binding sites for transcription

factors 

TRANSCRIBERS: DEL ROSARIO, GARCIA, ROMERO

 The Cell as a Unit of Health and Disease
 Typically results in transcriptional
silencing
DNA Methylation  Regulated by methyltransferases,
demethylating enzymes, and
methylated DNA-binding proteins 
Proteins which are believed to bnd to
noncoding regions and control long range
Chromatin Organizing looping of DNA for the regulation of spatial
Factor relationships between enancers and
promoters 
Evidence points out that dysregulation of the “epigenome” has a
central role in malignancy. Thus, epigenetic alterations, which are
reversible and are amenable to therapeutic intervention, are tested
in the treatment of various forms of cancer.
MICRO-RNA AND LONG NONCODING RNA
Encoded by genes that are transcribed but not translated.
 Micro-RNA (miRNA) (22 nucleotides)
o Do not encode proteins but functions to modulate translations
of target mRNAs into their corresponding proteins
o Regulates gene expression in eukaryotes by post-
translational silencing.
o Regulate multiple protein-coding genes allowing each miRNa
to co-regulate entire programs of gene expression
o miRNA genes transcription produces primary miRNA which
is processed within the nucleus to form pre-miRNA (single
RNA strand with secondary hairloop structures) . Pre-miRNA  Phosphatidylinositol
is exported out of the nucleus to be trimmed by the
cytoplasmic DICER enzyme to generate mature single-
stranded miRNAs that are associated to a multi-protein
aggregate called RISC (RNA-induced silencing complex).
Base pairing of the miRNA and the target mRNA directs the
RISC to induce mRNA cleavage or repress its translation
o miRNA biding specificity and gene silencing is determined by  Phosphatidylserine
the seed sequence of mRNAs in their 3'-UTR.
o Small interfering RNAs (siRNAs)
 RNA sequences that can be introduced experimentally into
the cells.
 Serve as substrates for Dicer and interacts with RISC like
the endogenous miRNA
 Used in knockdown technology (mRNAs are silenced by  Glycolipids and sphingomyelin
synthetic siRNAs to study gene function).
 Long-Noncoding RNA (lncRNA)
o modulate gene expression through:
Figure 2. Roles of lncRNA
o Examples:
1.) XIST, transcribed from X chromosome forms a repressive cloak
from which it is transcribed, resulting in gene silencing;
2.) lncRNA synthesized from enhancers often increase
transcription from gene promoters.
Normally compartmentalized within membrane-bound
intracellular organelles to decrease or eliminate the risking
TRANSCRIBERS: DEL ROSARIO, GARCIA, ROMERO
damage to other cellular constituents of potentially injurious
degradative enzymes or reactive metabolites. This also allows
creation of unique intracellular environments (high pH, high
calcium) that selectively regulate enzyme functions
.
Figure 3. Basic Subcellular Components of Cells
PLASMA MEMBRANE: PROTECTION
AND ACQUISITION
Asymmetric partitioning of phospholipids is important, as follows:
o On the inner membrane leaflet
o Can be phosphorylated and serve as electrostatic scaffold
for intracellular proteins
o Can also be hydrolized by phospholipase C to generate
DAG and IP3
o On inner leaflet and confers a negative charge for
electrostatic interactions
o May serve as an “eat me” signal when it flips to the
extracellular face which happens during apoptosis
o In platelets, serves as a cofactor in clotting of blood
o Preferentially expressed on extracellular face
o Glycolipids, especially gangliosides, are important in cell-
cell and cell-matrix interactions (e.g. Inflammatory cell
recruitment ad sperm-egg interactions)
CELLULAR HOUSEKEEPING
 Lipid rafts
o Distinct lipid domains formed by predilection of certain
membrane components for association through horizontal
interactions.
Plasma membrane is studded with a variety of proteins and
glycoproteins that are involved in ion and metabolite transport;
fluid-phase and receptor-mediated uptake of macromolecules; and
cell ligand, cell-matrix, and cell-cell interactions. Arrangements of
proteins that confer differences in function are as follows:
 Integral (contains positively charged amino acids) or
Transmembrane Proteins
 Proteins synthesized in cytosol and post-translationally
attached to prenyl groups or fatty acids, that insert into the
cytosolic side of the membrane
 GPI (glycosylphosphatidylinositol) anchors on extracellular
face of membrane that allow insertion of proteins into
membrane
 Noncovalent association of peripheral proteins with
transmembrane proteins
Many plasma membrane proteins function together as large
complexes; these may either be aggregated under the control of
chaperone molecules in the RER or by lateral diffusion in the
plasma membrane followed by complex formation in situ ( a
characteristic of many protein receptors).
The extracellular face of the membrane Is studded with
polysaccharides attached to integral membrane proteoglycans and
is termed as glycocalyx. This functions as a chemical &
mechanical barrier and involved in cell-cell & cell-matrix
interactions.
PASSIVE MEMBRANE DIFFUSION
 Small, nonpolar molecules like O2 and CO2 readily diffuse in lipid
bilayers
 The Cell as a Unit of Health and Disease
 Hydrophobic molecules (e.g. steroid based molecules like
estradiol and vitamin D) also easily passes
 Small polar molecules, smaller than 75 Da, (e.g. water, ethanol
and urea) can also cross
 If large volumes of water are transported, aquaporins augment
passive water transport.
 The membrane is impermeant to ions no matter how small, due
to their charge and high degree of hydration
CARRIERS AND CHANNELS
 Channel Proteins
o Create hydrophilic pores which permit rapid movement of
solutes (usually restricted by size and charge)
 Carrier Proteins
o Bind specific solute and undergo conformational changes to
transport the ligand
o Transport is relatively slow
o Accomplishes active transport using energy released by ATP
hydrolysis or a coupled ion gradient
 Includes multi drug resistance (MDR) protein which pumps
polar compounds (e.g. chemotherapeutic drugs) out of cells
Since the cytosol is rich in charged metabolites and protein
species that attract a large number of counterions that increase
cellular osmolarity, cells need to constantly pump out small
inorganic ions (Na+ and Cl-)
Transport mechanisms also regulate intracellular and
intraorganellar pH; most cytosolic enzymes prefer to work at pH
7.4 whereas lysosomal enzymes function at pH 5 or less
RECEPTOR-MEDIATED AND FLUID PHASE UPTAKE
 Endocytosis occurs by:
o Caveolae
 Noncoated invaginations of the plasma membrane that take
up small molecules--- including some vitamins.
 Associated with GPI-linked molecules, cAMP binding
proteins, SRC-family kinases, and the folate receptor
 Potocytosis
 internalization of caveolae with any bound molecules and
associated ECF
 “cellular sipping”
 Implicated in the regulation of transmembrane signalling
and/or adhesion via internalization of receptors and
integrins
o Clathrin-mediated/Receptor-mediated
 For uptake of bigger molecules
 After binding to specific cell-surface receptors,
internalization occurs through a membrane invagination
driven by a coat of clathrin
 Major uptake mechanism for certain macromolecules
(transferrin and LDL)
 Receptors are resistant to harsh environments in the
lysosome and are recycled back to the plasma membrane.
 Familial hypercholesterolemia results from defects in
receptor-mediated transport of LDL
 Pinocytosis
 “cellular drinking”
 a fluid phase process during which the plasma membrane
invaginates and is pinched off to form a cytoplasmic
vesicle
 begins at a specialized region of the membrane called the
clathrin-coated pit which invaginates and pinches off to
form clathrin-coated vesicle
 Each vesicle fuses with an early endosome where they
discharge their contents for digestion and further passage
to the lysosome
 Exocytosis
o Process by which proteins synthesized and packaged within
the RER and Golgi are concentrated in secretory vesicles
which fuse with the plasma membrane
 Transcytosis
o movement of endocytosed vesicles within the apical and
basolateral compartments of cells
o for transferring large amounts of intact proteins across
epithelial barriers (e.g. ingested Ab in maternal milk across
intestinal epithelia)
o Plays a role in the increased vascular permeability seen in
healing wounds and in tumors
TRANSCRIBERS: DEL ROSARIO, GARCIA, ROMERO
CYTOSKELETON AND CELL-CELL INTERACTIONS
Cytoskeleton
 Confers the ability of cells to adopt a particular shape, maintain
polarity, organize the relationship of intercellular organelles, and
move about
 In eukaryotes, divided into:
A.) Actin microfilaments
 5-9 nm fibers from G-actin, the most abundant cytosolic protein
in cells
 G-actin polymerize into F-actin which assemble into bundles and
networks to control cell shape and movement
B.) Intermediate filaments
 10 nm fibrils which have characteristic tissue-specific patterns of
expression that can be useful for assigning a cell of origin for
poorly differentiated tumors
 predominantly in polymerized form but do not reorganize like
actin
 impart tensile strength and allow cells to bear mechanical stress
 major structural proteins of skin and hair
 Lamin A, B, and C
o Nuclear lamina of all cells
o For normal nuclear morphology and transcription
o Mutations may lead to muscular dystrophy, progeria, etc.
 Vimentin - in mesenchymal cells
 Desmin - in muscle cells
 Neurofilaments - impart strength and rigidity on axons of
neurons
 Glial fibrillary acidic protein - glial cells
 Cytokeratins
o Can be used as cell markers to differentiate cells
o Subdivided into acidic (type 1) and neutral/basic (type 2)
C.) Microtubules
 25 nm fibrils made of α- and β-tubulin arranged into hollow tubes
with a defined polarity
 “-” end is embedded In a microtubule organizing center (MTOC
or centrosome) near the nucleus and is associated with
centrioles
 “+” end recedes or elongates depending on stimuli
 can serve as connecting cables for “molecular motor” proteins
that use ATP:
o Kinesins (- to +) or anterograde transport
o Dynein (+ to -) or retrograde transport
 also participate in sister chromatid separation during mitosis
 form motile cilia and flagella
CELL-CELL INTERACTIONS
Conferred by the formation of junctions that provide mechanical
links and enable surface receptors to recognize ligands on other
cells.
Types of Cell Junctions:
 Occluding (tight) junctions
o Seal adjacent cells to create a continuous barrier that restricts
paracellular movement of ions and other molecules
o Made of occludin, claudin, zonulin and catenin
o Allows the segregation of apical and basolateral domains of
cells to maintain cell polarity
 Anchoring junctions (desmosomes)
o Attach cells to other cells or to ECM
o Designated as a spot desmosome or macula adherens if
the adhesion focus (from cadherins called desmogleins and
desmocollins) is between cells, and is small and rivet-like.
o Known as a hemidesmosome when the adhesion focus
(made of connector proteins called integrins) attaches cell to
ECM
o If adhesion domains (made of E-cadherin molecules) occur
as broad bands between cells, denoted as belt desmosomes
o Focal adhesion complexes
 Macromolecular complexes that can be localized at
hemidesmosomes, that can generate intracellular signals
when cells are subjected to sheer stress
 Communicating (gap) junctions
o Mediate the passage of chemical or electrical signals from
one cell to another
o Made from connexins which form a dense, planar array of
pores (called connexons) which allow passage of ions,
nucleotides, sugars, amino acids, vitamins, and other small
molecules
 The Cell as a Unit of Health and Disease
o Permeability is decreased by lowered pH and increased Ca2+
o For example, allows myocardium to behave like a functional
syncytium
BIOSYNTHETIC MACHINER: ER AND GOLGI
The structural proteins and enzymes of the cell are constantly
renewed by ongoing synthesis tightly balanced with intracellular
degradation.
 Endoplasmic Reticulum
o Site for synthesis of all the transmembrane proteins and lipids
for plasma membrane and cellular organelles
o Initial site for synthesis of all molecules destined for export
out of the cell
o In cystic fibrosis, a CFTR protein mutation causes the
absence of a single amino acid (phe508), which leads to
misfolding, ER retention, and degradation of the CFTR protein
o ER stress response (aka unfolded protein response/ UPR)
may result if the misfolded proteins exceeds the capacity of
ER to edit and degrade them, leading to apoptosis
 Golgi Apparatus
o Receives proteins and lipids shuttled from the RER if these
molecules are destined for other organelles or for extracellular
export
o Progressively modifies proteins from cis (near ER) to trans
(near plasma membrane)
 e.g. pruning and modification of N-linked oligosaccharides
and O-linked oligosaccharides (sugar moieties linked to
serine and threonine)
o Prominent in cells specialized for secretion, including goblet
cells of intestine, bronchial epithelium, and plasma cells
WASTE DISPOSAL:
LYSOSOMES AND PROTEASOMES
 Lysosomes
o Membrane bound organelles containing acid hydrolases that
function best at pH ≤ 5
o Contain enzymes that are initially synthesized in the ER and
then tagged with a mannose-6-phosphate residue(M6P)
residue within the Golgi
o The other macromolecules destined for catabolism in
lysosomes arrive via one of these ways:
 Material internalized by pinocytosis or endocytosis fuses
with early endosome to late endosome (where significant
digestion begins), and ultimately into the lysosome
 Autophagy of obsolete organelles and large, denatured
protein complexes
 Phagosomes formed from phagocyosis of microorganisms
or large fragments of matrix or debris fuse with lysosomes.
 Proteasomes
o Degrade denatured or misfolded proteins, or proteins marked
by ubiquitin into small (6 to 12 amino acids) fragments
CELLULAR METABOLISM AND
MITOCHONDRIAL FUNCTION
 Mitochondria contain their own DNA (about 1% of total DNA)
encoding roughly 1% of the total cellular proteins and
approximately 20% of the proteins involved in oxidative
phosphorylation. Associated disorders may be X-linked,
autosomal, or maternally inherited.
 Energy Generation
o Intermembrane space- site of ATP synthesis
o Thermogenin- allows the generation of heat from electron
transport chain instead of energy generation
o May produce ROS thus mitochondria have relatively short half
life of 1-10 days
 Intermediate metabolism
o Warburg Effect - rapidy growing cells (both benign and
malignant) upregulate glucose and glutamine uptake and
decrease ATP production per glucose molecule
 Cell death
o Necrosis
 External cellular injury can induce the formation of
mitochondrial transition pores which allow the dissipation
of proton potential so that ATP generation fails and the cell
dies
o Apoptosis
 In the intrinsic pathway, mitochondria become leaky to
cytochrome C which forms a complex with other proteins
and activates caspases
 In neurodegenerative disorders like Alzheimer's
TRANSCRIBERS: DEL ROSARIO, GARCIA, ROMERO
 Loss of cellular communication and “social controls” that
maintain normal relationships of cells can variously lead to
unregulated growth (cancer) or an ineffective response to an
extrinsic stress (as in shock)
CELLULAR ACTIVATION
 Extracellular signals determine whether:
o Cell lives
o Cell dies
o Cell remains quiescent
o Cell is stimulated to perform its specific function
 Loss of cellular communication can lead to:
o Unregulated growth (e.g. cancer)
o Ineffective response to an extrinsic stress (e.g. shock)
CELL SIGNALLING
 Cells require certain inputs to continue living
 Absence of appropriate exogenous signals --> cells die by
apoptosis
CLASSIFICATION OF SIGNALS WHICH CELLS RESPOND TO
1.) Damage to Neighboring Cells and Pathogens
 Cells have innate capacity to sense and respond to danger
signals from damaged cells and foreign invaders
2.) Contact with Neigboring Cells
 Mediated through (a) adhesion molecules and/or (b) gap
junctions
 Gap Junction Signaling – accomplished between adjacent
cells via hydrophilic connexons which permit movement of small
ions, metabolites, and potential 2nd messengers
3.) Contact with Extracellular Matrix (Ecm)
 Mediated through integrins (for leukocyte attachment)
4.) Secreted Molecules
 Most important secreted molecules:
o Growth Factors
o Cytokines – mediators of inflammation & immune responses
o Hormones
CLASSIFICATION OF EXTRACELLULAR SIGNALING
(BASED ON DISTANCE OF SIGNAL FUNCTION)
PARACRINE SIGNALING
 Cells in immediate vicinity are affected
 Needs minimal disffusion
 Signal must be (1) rapidly degraded, (2) taken up by other cells,
or (3) tapped in the ECM
AUTOCRINE SIGNALING
 Molecules released affect the same cell
 Used to:
o guide group of cells undergoing synchronous differentiation
o amplify or inhibit a response via feedback
SYNAPTIC SIGNALING
 Involves neurons which secrete neurotransmitters at synapses
onto their target cell/s
ENDOCRINE SIGNALING
 Mediator is release through the bloodstream
 Target cells are distant
CLASSIFICATION OF RECEPTORS
(BASED ON THEIR LOCATION)
 Signaling molecules (ligands) --> binds to receptors --> initiates
cascade of events --> cellular response achieved
 At physiologic concentration, ligands have high affinities to their
receptors
INTRACELLULAR RECEPTORS
 Transcription factors activated by lipid-soluble ligands (e.g. Vit D
and steroid hormones)
 In some cases, ligand diffuses into adjacent cells to activate the
cascade (e.g. NO)
CELL-SURFACE RECEPTORS
 Generally transmembrane proteins
 Extracellular domains bind the ligands
 Ligand-binding can cause:
o opening of ion channels
o activation of an associated GTP-binding regulatory protein (G
Protein)
o activation of endogenous or associated enzyme
o triggering of a proteolytic event or change in protein binding or
stability which activates a latent transcription factor
 The Cell as a Unit of Health and Disease

 Functions as molecular connectors that physically link different

 *Note: enzymes
o 2nd & 3rd = associated with growth factor signaling pathways  Promote assembly of complexes
o 4th = common feature of pathways regulating normal  Can be…
development o integral membrane proteins OR
o cytosolic proteins
SIGNAL TRANSDUCTION PATHWAYS  May contain few specific domains to mediate protein-protein
 Binding of a ligand induces clustering of receptors (receptor interaction
cross-linking) and other forms of physical perturbations
 Perturbations change physical state of intracellular domain TRANSCRIPTION FACTORS
which then triggers additional biochemical events for signal  Used by most signal transduction pathways to influence cellular
transduction function
 Modulates gene transcription through their activation and
CLASSIFICATION OF RECEPTORS nuclear localization
(BASED ON SIGNALING MECHANISMS USED)  Conformational change can
 Leads to formation or modification of intermediates and/or o can allow translocation to the nucleus OR
activation of enzymes to generate active transcription factors o can expose specific DNA or protein binding motifs
which would enter the nucleus  May drive expression of relatively limited set of genes

RECEPTORS ASSOCIATED WITH KINASE ACTIVITY  MYC & JUN – two of the TFs needed for growth
 Uses downstream phosphorylation  P53 – TF that lead to growth arrest
 Alteration of receptor geometry…
o elicits intrinsic receptor protein kinase activity OR  Have modular designs with domains that (1) bind DNA and (2)
o promotes enzymatic activity of recruited intracellular kinases that interact with other proteins:
 Intracellular Kinases: o DNA-binding domain – permits specific binding to short
o Tyrosine Kinases DNA sequences
o Serine/Threonine Kinases  Most TFs bind with long-range regulatory elements like
o Lipid Kinases enhancers which are mostly located close to the genes
 For every phosphorylation event, there is also a phosphatase
(removes phosphate) to modulate signaling o Protein-Protein Interaction Domain – needed to induce
transcription
A.) RECEPTOR TYROSINE KINASE (RTKs)  Directly or indirectly recruits the following:
 Integral membrane proteins  histone modifying enzymes
 Used by…  remodeling complexes
o Insulin  RNA polymerase (for RNA synthesis)
o Epidermal growth factor
o Platelet derived growth factor GROWTH FACTORS AND RECEPTORS
 Ligand bindings activates intrinsic tyrosine kinase domains in  Growth Factors – stimulate the activity of genes required for
the cytoplasmic tails cell growth and division
 Expressed genes can:
B.) NON-RECEPTOR TYROSINE KINASE o promote entry of cells into the cell cycle
 Used by receptors with no intrinsic catalytic activity o relieve blocks on cell cycle progression – promotes replication
 Phosphorylates specific motifs on the receptor or other proteins o prevent apoptosis
 SRC – homolog of Rous sarcoma virus transforming protein; o enhance biosynthesis of cellular components required for a
prototype for one of the important NRTKs mother cell to give rise to two daughter cells
 SRC-homology 2 (SH2) – binds to receptors phosphorylated by  Growth factors can also drive non-growth activities (e.g.
another kinase causing aggregation of multiple enzymes migration, differentiation, synthetic capacity)
 SRC-homology 3 (SH2 ) – mediate protein-protein interactions,  Involved in cell proliferation during steady state or after injury
often proline-rich domains  Many growth factor pathway genes are proto-oncogenes -->
when gain-of-function mutation occurs, they are converted to
G-PROTEIN COUPLED RECEPTORS oncogenes
 Polypeptides that traverse the plasma membrane 7 times
(serpentine receptors) EPIDERMAL GROWTH FACTOR AND
 After ligand binding, receptor associates with intracellular GTP- TRANSFORMING GROWTH FACTOR-α
binding protein (G-Protein) which contains GDP  Belong to EGF family; binds to same receptors
 Binding of the two causes exchange of GDP for GTP  Produced by macrophages and epithelial cells
 Downstream receptor-mediated signaling result in generation of  Mitogenic for the following:
cAMP and IP3 o Hepatocytes
o Fibroblasts
NUCLEAR RECEPTORS o Epithelial cells
 Lipid-soluble ligands diffuse through the cell membrane and
forms receptor-ligand complex  EGF Receptor Family --> includes 4 membrane receptors with
 Complex binds with the nuclear DNA resulting in either intrinsic tyrosine kinase activity
activation or repression of transcription  EGFR1 – a.k.a. ERB-B1; mutations and/or amplification
frequently occur in cancers
OTHER CLASSES OF RECEPTORS  ERBB2 Receptor – a.k.a. HER2; overexpressed in a subset of
A.) RECEPTOR PROTEINS OF THE NOTCH FAMILY breast cancers
 Ligand binding to Notch receptors results to proteolytic cleavage
of receptor and subsequent nuclear translocation of cytoplasmic HEPATOCYTE GROWTH FACTOR
piece  Also known as scatter factor
 Effects:
B.) WNT PROTEIN LIGANDS o Has mitogenic effects on:
 Influences cell development through transmembrane Frizzled  hepatocytes
family receptors which regulate intracellular levels of B-catenin  epithelial cells (biliary, pulmonary, renal, mammary, &
 B-catenin – normally targeted for ubiquitin degradation epidermal)
 WNT binding to Frizzled recruits “Disheveled” that disrupts the o Acts as a morphogen in embryonic development (i.e.
degradation-targeting complex influences pattern of tissue differentiation)
 B-catenin – once stabilized, it translocates to the nucleus to o Enhances hepatocyte survival
form a transcriptional complex  Produced by:
o Fibroblasts - major
MODULAR SIGNALING PROTEINS, HUBS, & NODES o mesenchymal cells - major
 Any initial signal results in multiple diverging effects to contribute o endothelium
to the desired out come o non-hepatocyte liver cells
 Synthesis: Inactive precursor (pro-HGF) --> proteolytically
ADAPTOR PROTEINS activated by serine proteases at sites of injury
 Possess key roles in organizing intracellular signaling pathways  Receptor: MET – has intrinsic tyrosine kinase activity;
frequently mutated in renal and thyroid papillary carcinomas

TRANSCRIBERS: DEL ROSARIO, GARCIA, ROMERO

 The Cell as a Unit of Health and Disease

o phosphorylates Smads --> forms heterodimers with Smad4

PLATELET-DERIVED GROWTH FACTOR which allows it nuclear translocation and association with
 Composed of two chains (designated by a pairs of letters) DNA-binding proteins
 Constitutively Active Isoforms:
o AA PRO-INFLAMMATORY ANTI-INFLAMMATORY
o AB EFFECTS EFFECTS
o BB  Production of collagen,  Inhibits lymphocyte
 Isoforms Needing Proteolytic Cleaveage: fibronectin, and proliferation
o PDGF-CC proteoglycans
o PDGF-DD  Inhibits collagen degradation  Inhibits leukocyte activity
 Stored in platelet granules and released upon platelet activation by decreasing MMP activity
 Produced by: and increasing activity of
o platelets – major tissue inhibitors of
o activated macrophages proteinases (TIMPs)
o endothelium  Drives fibrosis in lung, liver,
o smooth muscle cells and kidneys in chronic
o tumors inflammation
 Isoforms exert effect by binding to PDGFR-α and –β
 Effects: INTERACTION WITH THE EXTRACELLULAR MATRIX
o Induces fibroblast, endothelial, and smooth muscle cell Extracellular Matrix
proliferation and matrix synthesis  a network of interstitial proteins that constitutes a significant
o Chemostatic for aforementioned cells causing recruitment of proportion of any tissue
cells into areas of injury and inflammation  Cell interactions with ECM are important for development,
healing and maintenance of normal tissue architecture
VASCULAR ENDOTHELILA GROWTH FACTOR  Is constantly being remodelled.
 Belongs to a family of homodimeric proteins:  Its synthesis and degradation accompanies tissue changes
o VEGF-A --> major angiogenic factor
o VEGF-B --> involved in embryonic vessel development KEY FUNCTIONS OF ECM
o VEGF-C --> for angiogenesis and lymphatic development  Mechanical support- for cell anchorage, migration and
o VEGF-D --> for angiogenesis and lymphatic development maintenance of polarity
o PIGF (Placental Growth Factor) - involved in embryonic  Control of cell proliferation - binds and displays growth factors
vessel development and by signalling through cellular receptors
 Functions:  Scaffolding for tissue renewal - basement membrane damage
o Maintains normal adult endothelium --> highest expression is results to defective tissue regeneration and repair
at epithelial cells adjacent to fenestrated epithelium  Establishment of tissue microenvironment - BM separates
 podocytes in the kidneys epithelium from connective tissue
 choroid blexus in the brain
 pigment epithelium in retina 2 BASIC FORMS
o Endothelial cell migration --> proliferation (capillary sprouting)  Interstitial matrix
--> formation of the vascular lumen o Three dimensional amorphous gel
o Induces vascular dilation and increased vascular permeability o in between cells and CT, and in between parenchymal
 Main Inducer: Hypoxia-Induced Factor 1 (HIF-1) epithelium and supportive vascular and smooth muscle
 Other Producers: structures
o PDGF o From mesenchymal cells (fibroblasts)
o TGF-α o Made up of fibrillar and non fibrillar collagens, fibronectin,
 Receptors: elastin, proteoglycan and hyaluronate
o VEGFR-1
o VEGFR-2 --> highly expressed in endothelium; most important  Basement membrane
for angiogenesis o Flat, lamellar “chicken wire” mesh
o VEGFR-3 o Despite being a membrane, it is actually porous
o From underlying epithelial cells and mesenchymal cells
FIBROBLAST GROWTH FACTOR o Made up of type IV non fibrillar collagen and laminin
 Family of growth factors with more than 20 members
 Best characterized fibroblasts: COMPONENTS OF THE ECM
o Acid FGF FIBROUS STRUCTURAL PROTEINS
o Basic FGF  Collagen
 Keratinocyte Growth Factor (KGF) --> a.k.a.FGF-7 o Made up of three separate polypeptide chains braided
 Released FGFs bind with heparin sulfate in ECM and then into a triple helix
serves as the reservoir for inactive factors (later on to be o There are 30 types of collagen
released by proteolysis) o Fibrillar Collagens
 Transduces signals through 4 Tyrosine Kinose receptors  Types I, II, III and V
 Contributes to:  Form linear fibrils stabilized with hydrogen bond
o wound healing  major constituent in CT in bone, tendon, cartilage,
o responses blood vessels and skin
o hematopoiesis  Vitamin C- impt for crosslinking of triple helices.
o development Deficiency causes bone deformities in children and
easy bleeding in any age
TRANSFORMING GROWTH FACTOR-β  Genetic defects include Ehlers Danlos syndrome and
 3 Isoforms: osteogenesis imperfecta
o TGF-β1 – has the most widespread dsitribution o Non- Fibrillar Collagens
o TGF-β2  Type IV, VII
o TGF-β3
 Regulate collagen fibril diameters and collagen-
 Belong to a family which includes:
collagen interactions via FACITS (fibril associated
o Bone Morphonegic Proteins (BMP)
collagen with interrupted triple helices)
o activins
 Promote anchoring fibrils to basement membrane in
o inhibins
strat. Squamous epithelium (type VII)
o Mullerian inhibiting substance (MIS)
 Has multiple and often opposing effects depending on the tissue
 Elastin
and concurrent signals (i.e. pleiotropic)
o gives the ability of recoil and recovery of shape to tissues
o has a central elastin core with fibrillin
 TGF- β1 – Produced as precursors by:
o Important for large BV and cardiac valves.
o Platelets
o In Marfan syndrome, fibrillin defect causes skeletal
o Endothelium
abnormalities and weakened aortic walls
o Mononuclear inflammatory cells
WATER HYDRATED GELS
 Receptors: Type I and Type II
 Proteoglycan
o with serine/threonine kinase activity

TRANSCRIBERS: DEL ROSARIO, GARCIA, ROMERO

 The Cell as a Unit of Health and Disease

o Form highly hydrated compressible gels that resists
compression
o Provides lubrication in joints
o Serve as reservoir for growth factors
o Made up of glycosaminoglycans
o Negatively charged densely packed sulphated sugars
contribute pulls cations which also cause osmotic pull of
water
 Hyaluronan
o Hyaluronic acid polymer
o Test tube brush like
o Linked with GAG
ADHESIVE GLYCOPROTEIN
 Fibronectin
o Large (450 kD) disulphide linked heterodimer
o Exists in plasma and tissue forms
o Synthesized by many cells including fibroblasts, monocytes
and endothelium
o Provides scaffolding for ECM deposition, angiogenesis and
reepithelialisation
 Laminin
o Most abundant glycoprotein in the BM
o Connects cells to type IV collagen and heparan sulfate
o Modulates cells proliferation, differentiation and motility
 Integrins
o Allow cells to attach to ECM constituents such as laminin
and fibronectin
o Integrins on leukocytes are essential for firm adhesion
and transmigration across the epithelium
o Integrins attach to ECM components via a tripeptide
arginine-lysine-aspartic acid motif (RGD)
o Binding through integrin receptors trigger signalling
cascades for cell locomotion, proliferation, shape and
differentiation
 Can only produce cells that are normal constituents of a
particular tissue
 Hematopoietic stem cells
o Most extensively studied adult stem cell
o Can be used to repopulate marrows depleted after
chemotherapy or for correction of blood cell defects
 Mesenchymal stem cells
o Multipotent cells that can differentiate to different stromal cells
 Chondrocytes
 Osteocytes
 Adipocytes
 Myocytes
REGENERATIVE MEDICINE
 Theoretically, ES cells and adult stem cells can repopulate
damaged tissues or to construct organs
 Difficulties in this field is encountered in introducing and
functionally integrating the replacement cells
 Difficulties also arise in the immunogenicity of stem cells
o Most adult stem cells and ES cells express HLA molecules
o Effort is given to find totipotent ES cells which are derived
from the patient to be implanted
o Genes have been identified to reprogram somatic cells to
achieve the stem-ness of the ES cells – induced pluripotent
cells (iPC)
 Genomic editing
o A process using a nuclease called C9 used together with
guide RNAs called CRISPRs
o Used to selectively ALTER or CORRECT DNA sequences

MAINTAINING CELL POPULATIONS

PROLIFERATION AND THE CELL CYCLE

 Fundamental to development, homeostasis and replacement of
dead or damaged cells
 The Cell Cycle:
o G1 - presynthetic Growth
o S - DNA Synthesis
o G2 - premitotic Growth
o M - mitotic phase
o G0 - cells not actively cycling
 Cells can enter G1 from the G0 pool or after a mitosis for
continuously proliferating cells
 Non fidelity of DNA replication or cofactor deficiency arrests the
cell cycle at transition points
o Controlled by cyclins and cycin dependent kinases (CDKs)
o G1-S checkpoint - monitors DNA integrity
o G2-M checkpoint - ensures accurate genetic replication
 When cells detect irregularities, the cell cycle is delayed and
DNA repair mechanisms take place
 If the genetic derangement is severe, the cell may undergo
apoptosis
 Cell cycle checkpoints are modulated by cyclin dependent
kinase inhibitors (CDKIs)
 Defect in CDKIs allow cells to multiply with damaged DNA,
promoting malignant tumors
 Growth factor signalling does not only activate cell cycle
progression, it also activates changes in cellular metabolism
o Warburg Effect- increased cellular uptake of glucose and
glutamine, increased glycolysis and decreased oxidative
phosphorylation. (fixed in cancer cells)

STEM CELLS
 Gives rise to various differentiated tissues
 In adults, they replace damaged cells and maintain tissue
populations
 Two important properties
o Self-renewal
o Asymmetric division- differentiation of one daughter cell to a
mature one and the other remains undifferentiatied
 Two varieties
o Embryonic Stem cells (ES cells)
 Present in the inner cell mass of the blastocyst.
 Have limitless cell renewal capacity
 Can give rise to every cell in the body (totipotent)
o Tissue stem cells (adult stem cells)
 Associated with differentiated cells within a tissue
 Protected within stem cell niches

TRANSCRIBERS: DEL ROSARIO, GARCIA, ROMERO