Leicester Warwick Medical School

Cellular Adaptations
Dr Gerald Saldanha
Department of Pathology Email: gss4@le.ac.uk

Introduction
This presentation will .
Focus on adaptive responses in cell growth & differentiation Describe cell signalling pathways Introduce the cell cycle

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

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.

Signalling molecules
Most signalling molecules cannot pass through the cell membrane
Their receptors are in the cell membrane

Small hydrophobic signal molecules can diffuse directly into the cell cytoplasm
Their receptors are cytoplasmic or nuclear

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)

Receptors
There are three main classes of receptors. Ion-channel-linked receptors G-protein-linked receptors Enzyme-linked receptors

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

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

G proteins
Some G proteins directly regulate ion channels Others activate adenylate cyclase, thus increasing intracellular cyclic AMP Some activate the enzyme Phospholipase C, thus increasing intracellular inositol triphosphate (IP3) and Diacylglycerol (DAG)

Enzyme-linked receptors
Many receptors have intracellular domains with enzyme function Most are receptor tyrosine-kinases They phosphorylate tyrosine residues in selected intracellular proteins These receptors are activated by growth factors, thus being important in cell proliferation

Receptor tyrosine kinases

Receptor tyrosine kinase activation results in assembly of an intracellular signalling complex This complex activates a small GTP-binding protein, 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

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 important transcription factors

Signalling pathway interactions

There are many signalling molecules and receptors A given cell expresses only a subset of receptors Different intracellular signalling pathways interact This enables cells to respond appropriately to complex combinations of signals

Cell signalling and proliferation

Animal cells proliferate when stimulated by growth factors 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

The cell cycle

The eukaryotic cell cycle consists of distinct phases The most dramatic events are nuclear division (mitosis) and cytoplasmic division (cytokinesis) This is the M phase The rest of the cell cycle is called interphase which is, deceptively, uneventful During interphase the cell replicates its DNA, transcribes genes, synthesises proteins and grows in mass

Phases of the cell cycle

S phase DNA replicates M phase nucleus divides (mitosis) and cytoplasm divides (cytokinesis) G1 phase gap between M and S phase G2 phase between S and M phase

Cell cycle control

Cell cycle machinery is subordinate to a cell cycle control system The control system consists mainly of protein complexes These complexes consist of a cyclin subunit and a Cdk subunit The cyclin has regulatory function, the Cdk catalytic function

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 key proteins in the cell

Cell cycle control

Different cyclin-Cdk complexes trigger different cell cycle steps Some drive the cell into M phase, others into S phase The cell cycle control system has in-built molecular breaks (checkpoints) The checkpoints ensure that the next step does not begin until the previous one is complete

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

The G1 checkpoint
This checkpoint is influenced by the action of cyclin-dependant kinase inhibitors (CKIs, e.g. p21, p16) E.g. p53 senses DNA damage and induces p21 expression CKIs inactivate cyclin-Cdk complexes

Cellular adaptations of growth and differentiation

Cells must respond to a variety of stimuli 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 of growth and differentiation depends in part on their ability to divide

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

Cellular proliferative capacity

Some cells dismantle their cell cycle control 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 cell cycle. These are permanent cells

Growth and differentiation responses

Hyperplasia Hypertrophy Atrophy Metaplasia

Hyperplasia Increase in the number of cells in an organ or tissue, which may then have an increased size

Hyperplasia: causes
Hyperplasia can only occur in tissues containing labile or stable cells Hyperplasia may occur under pathological or physiological conditions

Physiological Hyperplasia
Hormonal e.g. endometrium Compensatory, e.g. partial hepatectomy
TGF alpha, HGF TGF beta

Pathological hyperplasia
Excessive hormone/growth factor stimulation Often occurs alongside hypertrophy Associated with increased risk for cancer E.g. Prostate, endometrium

Hypertrophy

An increase in cell size, and resultant increase in organ size

Hypertrophy: causes
Occurs in permanent cells Due to synthesis of more cellular structural components Physiological or pathological causes

Physiological hypertrophy
Increased functional demand, e.g. skeletal muscle
Mechanical

Hormonal, e.g. Uterus in pregnancy

Usually a combination of hypertrophy and hyperplasia

Pathological hypertrophy
Increased functional demand e.g. cardiac muscle
Hypertension valvular heart disease

Atrophy

Shrinkage in cell size by loss of cell substance

Term is often used loosely to describe reduced organ size that may be related to cell loss rather than shrinkage

Atrophy: causes
Reduced workload Loss of innervation Reduced blood supply Inadequate nutrition Loss of endocrine stimulation Ageing

Metaplasia

Reversible change of one adult cell type to another adult cell type

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. squamous cell carcinoma of the bronchus Metaplasia in mesenchymal tissues is often less clearly adaptive

Hypoplasia
Incomplete development of an organ with reduced cell numbers

Summary
Cells communicate through signalling pathways Signalling pathways influence the cell cycle control system This determines a cells ability to divide A cells replicative capacity influences its adaptive responses to changes in the tissue environment