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PATHOLOGY (MONDAY)
The cell and cell injury:
STRUCTURE AND FUNCTION OF CELL COMPONENTS;
Nucleus The nucleus is composed principally of
deoxyribonucleic acid (DNA) in combination with a
protein (histone) within a ground substance. The
nucleic acid material (chromatin) stains well with
basic dyes such as haematoxylin and methylene blue, and
DNA can be stained specifically by the Feulgen
technique. Chromatin patterns vary from cell to cell.
The plasma cell, for example, has a distinctive
'cartwheel' pattern. The nucleus is separated from the
cytoplasm by a double membrane - the nuclear envelope containing circular holes 50 to 70 nm in diameter nuclear pores. The pores, which are usually crossed by
a diffuse membrane, probably represent the sites of
interchange between nucleus and cytoplasm.
Functions of the nucleus:
1. Replication of DNA
2. Production of messenger RNA
3. Synthesis of some nuclear proteins Nucleolus The
nucleus normally contains one or more small basophilic
structures nucleoli, composed of a dense network
(nucleolonema) enclosing paler areas (the pars
amorpha). The granules of the nucleolonema are thought
to represent newly-synthesized ribosome subunits which
pass out of the nucleus along with messenger RNA and
direct the synthesis of specific proteins in the
cytoplasm. Cytoplasm Cytosol differs from extracellular
fluid in having a high concentration of potassium,
magnesium and phosphate. Sodium is actively excluded by
the ATP-dependent 'sodium-pump' across the cell
membrane. Many functions reside in the cytosol or
cytoplasmic matrix, namely:
1. Glycolysis
2. Some reactions in gluconeogenesis
3. Activation and synthesis of some amino acids
4. Fatty acid synthesis
5. Mononucleotide synthesis
6. Phosphogluconate pathway
7. Second messenger signaling pathways Mitochondria
These round, ovoid, or sinuous cytoplasmic organelles
possess a complete outer trilaminar membrane and an
inner membrane which shows numerous infoldings termed
cristae. Although all mitochondria have this basic
structure there is considerable variability both in the
number and length of the cristae and in the number and
general outline of the mitochondria.
Cells with a high metabolic activity have large
mitochondria with numerous cristae, for example cardiac
muscle and gastric parietal cells. In the liver, whilst
the mitochondria are large, the cristae are sparse and
irregular. Mitochondria contain most of the enzymes of
the citric acid cycle and the energy derived from the
oxidation of acetyl Co-A in the cycle is used to
convert adenosine diphosphate to triphosphate oxidative phosphorylation.
Endoplasmic reticulum: All cells contain a system of
complex paired membranes enclosing small vesicles or
channels - the cisternae. These membranes form the
endoplasmic reticulum (ER) and are either studded with
ribosomes forming so-called rough ER or are devoid of
granules and are termed smooth ER. The main function of
the rough ER, together with free ribosomes in the
cytoplasm, is protein synthesis. Protein produced by
PATHOLOGY (WEDNESDAY)
PROTEOLYSIS AND PROTEIN FOLDING:
While it is self evident that rapid and efficient
proteolysis is central to the proper functioning of the
cell, it is only recently that the mechanisms
controlling proteolysis have begun to be understood.
For instance, there is a very close connection between
proteolysis and control of the cell cycle. Indeed a
single protein, cyclin B, which accumulates during the
Gi and S phases must be degraded for cells to exit
mitosis.
One of the major factors in the regulation of such
degradation is the protein ubiquitin. As its name
implies, this protein is highly conserved throughout
eukaryotes, and is unique in its ability to become
reversibly cross-linked to other proteins. In doing so
it is likely that ubiquitin serves as a movable binding
site for proteins that do not have complementary
structures and by bringing such proteins into close
association is an essential component of many important
proteolytic pathways. The proper functioning of newly
synthesised proteins is dependent upon them attaining
the correct three dimensional configuration.
The complex folding of polypeptides involved in this
process is controlled by other proteins which are
either enzymes promoting disulphide formation and
isomerisation, or members of a family of proteins which
stabilise unfolded and partially folded structures and
prevent the development of inappropriate intra- and
inter-chain bonds. They achieve this without themselves
becoming incorporated into the structure. These
proteins are termed chaperones and are vital to the
correct translocation, assembly, disassembly and
transport of polypeptides and protein oligomers. The
proteins first came to notice when found in excessive
amounts as part of the cellular response to high
temperature, hence the name 'heat-shock' proteins. Now
that it is appreciated that they are essential to
PATHOLOGY (FRIDAY)
CYTOKINE RECEPTORS:
Receptors consist of;
(i) an external domain which is the binding site for
the ligand
(ii) a transmembrane region which spans the cell
membrane
(iii) an intracellular domain which delivers the signal
to the cytosol Receptors may consist of a single
polypeptide chain on its own, e.g. EGF-R, a single
polypeptide chain plus a second helper protein, e.g.
IFN-,Y receptor, or two polypeptide chains, e.g. IGF-1
receptor. Receptors can be of high or low affinity,
e.g. IL-2, or they can have a different level of
response to different ligands, e.g. IGF-1 receptor
binding IGF-1 and insulin.
Receptor modulation is achieved by altering:
(i) the rate of synthesis and membrane insertion
(ii) receptor internalisation and recycling
(iii) receptor degradation via lysosomes
Signal transduction:
Following binding of cytokine with its appropriate
receptor there follows a cascade of events that
eventually (after several hours) lead to stimulation of
DNA synthesis and cell division or induction of MRNA
and protein synthesis. The mechanisms involved in this
'signal transduction' are highly complex. Some
receptors operate through activation of their internal
tyrosine kinase domain, e.g. erb-B family, PDGF-R,
IGF1-r; others transduce their signals via cytoplasmic
tyrosine or serine/threonine kinases, e.g. src, yes,
fgr; yet others operate through phospholipase-C
activity, e.g. crk.
These enzymes act through a series of intermediaries
and protein phosphorylation to 'switch on' DNA and
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