cell mechanism

8/6/2019 Cell Mechanism

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Leicester Warwick Medical School

Cellular Adaptations

Dr Gerald SaldanhaDepartment of Pathology

Email: [email protected]


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Introduction

This presentation will .

Focus on adaptive responses in cell growth

& differentiation

Describe cell signalling pathways

Introduce the cell cycle


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Control of cell growth

Cells in a multicellular organism

communicate through chemical signals

Hormones act over a long range

Local mediators are secreted into the

local environment Some cells communicate through direct

cell-cell contact


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Control of cell growth

Cells are stimulated when extra cellular

signalling molecules bind to a receptor

Each receptor recognises a specific protein

(ligand)

Receptors act as transducers that convert the

signal from one physical form to another.


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Signalling molecules

Most signalling moleculescannot pass through the cell

membrane Their receptors are in the cell

membrane

Small hydrophobic signalmolecules can diffuse directlyinto the cell cytoplasm Their receptors are cytoplasmic

or nuclear


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Signalling molecules Hormones

Insulin,

Cortisol

etc

Local mediators

Epidermal Growth Factor (EGF),

Platelet Derived Growth Factor (PDGF)

Fibroblast Growth Factor (FGF) TGFF

Cytokines, e.g. Interferons, Tumour necrosis factor (TNF)


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Receptors

There are three main classes of

receptors.

Ion-channel-linked receptors

G-protein-linked receptors

Enzyme-linked receptors


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Receptors

Ion channel-linked receptors

are important in neural

signalling G-protein and enzyme

linked receptors respond by

activating cascades of

intracellular signals These signals alter the

behaviour of the cell


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G-protein-linked receptors

G-protein-linked receptors activate a class

of GTP-binding proteins (G-proteins)

G proteins are molecular switches

They are turned on for brief periods while

bound to GTP

They switch themselves off by hydrolysing

GTP to GDP


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G proteins Some G proteins directly regulate ion

channels

Others activate adenylate cyclase, thusincreasing intracellular cyclic AMP

Some activate the enzyme

Phospholipase C, thus increasingintracellular inositol triphosphate (IP3)

and Diacylglycerol (DAG)


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Enzyme-linked receptors

Many receptors have intracellulardomains with enzyme function

Most are receptor tyrosine-kinases They phosphorylate tyrosine residues in

selected intracellular proteins

These receptors are activated by growthfactors, thus being important in cellproliferation


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R

eceptor tyrosine kinases

Receptor tyrosine kinase activation results in

assembly of an intracellular signalling complex

This complex activates a small GTP-bindingprotein, Ras

Ras activates a cascade of protein kinases that

relay the signal to the nucleus

Mutations that make Ras hyperactive are a

common way of inducing increased proliferation in

cancer


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Signalling: cytoplasm to nucleus

Many signalling cascades culminate in

activation of nuclear transcription factors

Transcription factors alter gene

expression

C-jun and c-fos ( that form an AP1

complex) and c-myc are three importanttranscription factors


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Cell signalling and proliferation

Animal cells proliferate when stimulated by growthfactors

These bind mainly to receptor tyrosine kinases These signalling pathways override the normal

brakes on proliferation

These brakes are part of the cell cycle control

system This ensures that cells divide only under

appropriate circumstances


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T

he cell cycle The eukaryotic cell cycle consists

of distinct phases

The most dramatic events are

nuclear division (mitosis) andcytoplasmic division (cytokinesis)

This is the M phase

The rest of the cell cycle is calledinterphase which is, deceptively,uneventful

During interphase the cellreplicates its DNA, transcribesgenes, synthesises proteins andgrows in mass


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Phases of the cell cycle

S phase DNA replicates

M phase nucleus divides

(mitosis) and cytoplasmdivides (cytokinesis)

G1 phase gap between

M and S phase

G2 phase between S and

M phase


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Cell cycle control

Cell cycle machinery is subordinate to acell cycle control system

The control system consists mainly ofprotein complexes

These complexes consist of a cyclin

subunit and a Cdk subunit The cyclin has regulatory function, theCdk catalytic function


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Cell cycle control

Cdk expression is constant, but cyclin

concentrations rise and fall at specific

times in the cell cycle

The Cdks are cyclically activated by cyclin

binding and by phosphorylation status

Once activated, Cdks phosphorylate keyproteins in the cell


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Cell cycle control

Different cyclin-Cdk complexes triggerdifferent cell cycle steps

Some drive the cell into M phase, others intoS phase

The cell cycle control system has in-builtmolecular breaks (checkpoints)

The checkpoints ensure that the next stepdoes not begin until the previous one iscomplete


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The G1 checkpoint

The G1 checkpoint has been widely studied

The retinoblastoma (Rb) protein plays a key

role at this checkpoint

The Rb protein function is determined by its

phosphorylation status

S phase cyclin-Cdk complexes

phosphorylate Rb


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Cellular adaptations of growth and

differentiation

Cells must respond to a variety ofstimuli that may be hormonal, paracrine

or through direct cell contact These stimuli may arise under

physiological or pathological conditions

The way that cells adapt in terms ofgrowth and differentiation depends inpart on their ability to divide


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Cellular proliferative capacity

Tissues can be classified according to

the ability of their cells to divide

Some tissues contain a pool of cells that

move rapidly from one cell cycle to the

next. These are labile cells


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Cellular proliferative capacity

Some cells dismantle their cell cyclecontrol machinery and exit the cell cycle

These cells are said to be in G0. Some of these cells can re-enter the cell

cycle when stimulated, e.g. by growth

factors. These are stable cells Others are unable to re-enter the cellcycle. These are permanent cells


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Growth and differentiation

responses

Hyperplasia

Hypertrophy

Atrophy

Metaplasia


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Hyperplasia

Increase in the number of cells in

an organ or tissue, which may then

have an increased size


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Hyperplasia: causes

Hyperplasia can only occur in tissues

containing labile or stable cells

Hyperplasia may occur under

pathological or physiological conditions


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Physiological Hyperplasia

Hormonal e.g. endometrium

Compensatory, e.g. partial hepatectomy

TGF alpha, HGF

TGF beta


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Pathological hyperplasia

Excessive hormone/growth factor

stimulation

Often occurs alongside hypertrophy Associated with increased risk for

cancer

E.g. Prostate, endometrium


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Hypertrophy

A

n increase in cell size, andresultant increase in organ size


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Hypertrophy: causes

Occurs in permanent cells

Due to synthesis of more cellular

structural components

Physiological or pathological causes


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Physiological hypertrophy

Increased functional demand, e.g.

skeletal muscle

Mechanical

Hormonal, e.g. Uterus in pregnancy

Usually a combination of hypertrophy and

hyperplasia


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Pathological hypertrophy

Increased functional demand e.g.

cardiac muscle

Hypertension

valvular heart disease


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Atrophy

Shrinkage in cell size by loss of cellsubstance

Term is often used loosely to describe

reduced organ size that may berelated to cell loss rather thanshrinkage


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Atrophy: causes

Reduced workload

Loss of innervation

Reduced blood supply

Inadequate nutrition

Loss of endocrine stimulation

Ageing


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Metaplasia

R

eversible change of one adult celltype to another adult cell type


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Metaplasia: causes

An adaptive response to various stimuli

New cell type is better adapted to

exposure to the stimulus The stimulus that induced metaplasia

may, later, induce cancer, e.g. squamouscell carcinoma of the bronchus

Metaplasia in mesenchymal tissues isoften less clearly adaptive


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Hypoplasia

Incomplete development of an organ

with reduced cell numbers


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Summary

Cells communicate through signallingpathways

Signalling pathways influence the cellcycle control system

This determines a cells ability to divide

A cells replicative capacity influences itsadaptive responses to changes in thetissue environment

cell mechanism

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