KINESIOL 1Y03 Lecture Notes - Lecture 18: Carbonic Anhydrase, Paracrine Signalling, Hepatocyte Nuclear Factor 4
23 Jun 2018
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Transcription and regulatory factors in GI malignancy
There are around 23000 genes in the human genome, different subsets of which are
differentially expressed according to:
Location: e.g. ileum c.f. duodenum
Cell type: e.g. mucosa c.f. submucosa
Time in development: foetal/neonatal/adult
Differentiation: crypt/villus, normal metaplastic dysplastic
Physiology: e.g. fed c.f. fasted c.f. re-fed states
Individual variations e.g. dietary factors and genetic polymorphisms
Gene subsets include: basic metabolism, epithelial transport (high in villous cell), antibody
production, hormone secretion, motility, replication (high in crypt cell) etc.
gene expression can be profiled using cDNA microarrays, which will show where different
genes are being expressed i.e. LOCAL DIFFERENTIATION
Bates et al 2002 showed that the duodenum has the most numbers of unique genes expressed,
the ileum still has many, the jejunum has few and the proximal colon has hardly any specific
genes expressed which are unique to that area
Mariadason et al 2005 showed, through gene expression profiling of intestinal epithelial cells
along the crypt-villous axis that these unique genes involving cell cycle, RNA processing,
cytoskeleton, transport, Wnt signallling are changed in the villous tip
Regulators of gene expression
1. Developmentally-programmed transcription factors
2. Cellular differentiation (age and location)
3. Hormones and receptors
a. Kinase phosphorlaytion pathways in the membrane
b. Steroid hormone family + orphan receptors in the nucleus
4. Direct nutrient effects
These regulators may affect: chromatin structure, DNA methylation, transcriptional activation
or post-transcriptional modification (alternative splicing, RNA stability, translational aspects)
Molecular origins of cancer: Molecular basis of CRC – S.D. Markowitx and M.M. Bertagnolli –
NEJM 2009 = READ!!
Germ-line genome and tumour genome, which affect germ-line gene expression and tumour
gene expression both influence tumour-host interaction tumour behaviour
Changes in gene expression in GI neoplasia include:
Deletion of specific genes
P53 – 60-70% frequency
FHIT – 60% frequency
amplification of specific genes
COX-2 – 70% frequency
VEGF – 50% frequency
Microsatellite instability – approximately 1/3 of tumours
Chromosomal changes (DNA aneuploidy / loss of heterozygosity – so only one
chromosomal gene is present and if it has mutations neoplasia) – approximately 2/3
of tumours
find more resources at oneclass.com
find more resources at oneclass.com
basially, learn all the genes…
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
There are around 23000 genes in the human genome, different subsets of which are differentially expressed according to: Physiology: e. g. fed c. f. fasted c. f. re-fed states. Individual variations e. g. dietary factors and genetic polymorphisms. Gene subsets include: basic metabolism, epithelial transport (high in villous cell), antibody production, hormone secretion, motility, replication (high in crypt cell) etc. Gene expression can be profiled using cdna microarrays, which will show where different genes are being expressed i. e. local differentiation. Mariadason et al 2005 showed, through gene expression profiling of intestinal epithelial cells along the crypt-villous axis that these unique genes involving cell cycle, rna processing, cytoskeleton, transport, wnt signallling are changed in the villous tip. Regulators of gene expression: developmentally-programmed transcription factors, cellular differentiation (age and location, hormones and receptors, kinase phosphorlaytion pathways in the membrane, steroid hormone family + orphan receptors in the nucleus, direct nutrient effects.
