Bio- Final exam notes.docx

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18 Jun 2013
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Lecture 18- Cancer
Four most common types of cancer in Canada
-Breast cancer
-Prostate cancer
-Lung cancer
-Colon cancer
-40% of women, 45% of men can expect to contract some kind of cancer in their lives
-Just less than 25% of women can expect to die from cancer, more than 25% of men can expect
to die from cancer
Likely factors contributing to cancer incidence in Canada
-older you are, the more likely you are at developing cancer
-Second most likely non-accidental cause of death (heart disease is the first)
-Risk factors: exposure to dietary risk factors, exposure to environment
-Lung and colon cancer suggest environmental risk factors
-Breast and prostate cancer suggest internal risk factors
-Balance of and interactions or internal and external factors that contribute to cancer
Role of cyclin/CDK complexes in cell cycle regulation
-Embryogenesis is rapidly diving cells
-Cells may actively cycle, sit in G0 or undergo apoptosis
-In the cell cycle there is a G1/s checkpoint that prevents cells from replicating their DNA if it is
damaged
-This is monitored by CDK (Cyclin Dependent Kinase)
-CDK is a protein
-It works by phosphorylating but only when it is bound to cyclin
-CDK/Cyclin phosphorylates it target proteins together to release the G1/s checkpoint and cells
proceed into S phase
-This is an example of post-translational regulation
-Constitutive expression- a gene that is transcribed continually compared to a facultative gene,
which is only transcribed as needed
-Production of cyclin is cyclic
-Another CDK/cyclin complex regulates movement from S phase into M phase
Uncontrolled Growth (1st reason): Role of proto-oncogenes and oncomirs in caner
-Proto-Oncogenes are essential for normal growth and development
-EGFR (Epidermal Growth Factor Receptor)
-It is a typical transmembrane protein
-Active site outside the cell that binds protein hormone EGF
-EGF stimulates the cell to divide
-EGFR signals on the outside of the cell phosphorylation cascade signals presence of EGF on
the outside of the cell causes the expression or no expression of certain genes in the nucleus
-Any step along the pathway could be expressed inappropriately, causing it to become cancerous
-When deregulated proto-oncogenes become cancerous and people call them oncogenes
-Mutation is EGFR, causing it to signal even when EGF is not present, will lead to the cell dividing
all the time up-regulation
-How might proto-oncogenes be „activated‟? Translocation issues, mutation in promoter
(causes the promoter to be more attractive to polymerase, resulting in more expression),
regulation problem with enhancers or repressors (enhancers become more effective than usual)
Uncontrolled Growth (2nd reason): Tumor suppressor genes and role of p53 gene
-Suppressor gene work against proto-oncogenes to ensure that cell division occurs at a regular
pace (genes that evolved to shut down rapid cell division)
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-TP53 is a master tumor suppressor gene; it codes a transcription factor that binds to the
promoters of many target genes
-When it binds to the target genes it can result in:
i) Increased DNA repair
ii) G1 arrest (cell cycle arrest, by blocking cyclin/CDK)
iii) Apoptosis
-A tumor suppressor gene may be inactivated through mutation in the gene itself, high
methylation (shutting off promoter), mutation in microRNAs (mistakenly shuts off tumor
suppressor gene, miRNAs highly important in gene expression and for diagnostic, particularly in
cancer, oncomirs (onco-microRNAs)
Explanation for why increased cancer risk can be inherited
-Most cancer in this country is sporadic (not due to family)
-However, for families that is at higher risk:
-Some sort of gene that‟s damaged or possessed certain epigenetic marks is being inherited
through the family
-People DO NOT inherit activated oncogene, more likely that they are inheriting an inactivated TS
gene mutation (epigenetic marking), inherit one defective allele for the gene, at some point in
their life, the other allele in one of their cells becomes inactivated too, leading to development of
tumors
-Relatedness does affect cancer
-(Example of BRCA1, which is a normal tumor suppressor and brca1 is the defected tumor
suppressor)
Explanation for why cancer incidence tends to increase with age
-Cancer is PROGRESSIVE!
-Age is a big factor, as you get older, you have more time to accumulate mutations
Role of stem cells in tumor growth
-Cancer may begin as alterations to gene expression in stem cells
-Most of your tissues have stem cells
-They know how to be every kind of cell (pluripotent)
-Stem cells divide differently than normal cells: stem cells make two daughter cells, one is a
progenitor cell, and one is a stem cell. Progenitor cell becomes differentiated cell (can be
anything)
-**BUT all three; stem cells, progenitor cells, and differentiated cells can suffer mutations and
become CANCER STEM CELLS
-Thus, tumors may be driven by cancer stem cells
Evidence that epigenetic regulation may be relevant in cancer
-Cancer is DEREGULATION!
-Uncontrolled growth can arise from upsetting the balance between the activities of gene products
that promote cell cycling vs. those gene products that suppress cell cycling
-Irregular (deregulation) versions of: promoting cell cycling, and suppressing cell cycling
Lecture 19- Molecular Homology
Strategies for determining if features are homologous
-Comparative genomics:
Sequence genomes
Genome annotation
Protein prediction
Align sequences
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Determine homology
-Sequencing is cheap but genome annotation (giving biological meaning to the sequence) is
harder
-Genome annotation by: gene prediction, regulatory elements, biological function through
similarity researches, and automatic processes
Sequences detected by annotation programs to detect open reading frames (ORF)
-Protein coding genes computer algorithm, detect promoter elements, intron/exon boundaries,
other conserved DNA motifs
-Identify homologous proteins and determine the extent of their sequence similarity with one
another and the unknown
-Align the sequences
-Identify structurally conserved and structurally variable regions
-To predict proteins, find the longest ORF (Open Reading Frame) (longest start to stop codon
space)
Characteristics that are, and are not, common between homologous genes
-Look for sequences that are similar!
-Arrange sequences to show regions of similarity (automated as well)
-Search database for similar sequences because similar sequences= -structural
-Functional
-Evolutionary relatedness
-If something is homologous, it is NOT because they have the same nucleotide sequence (that is
what blast shows you), it is very similar, but not identical
-Don‟t have the same protein sequence either, you see this after you translate the DNA sequence
to protein, still very very similar, but not perfectly identical
-Don‟t have the same length
-Don‟t have the same function
Usefulness of BLAST analysis of sequences in Genbank at NCBI
-NCBI (National Center for Biotechnology Information)
-It is a repository for genetic information
-Sequences databases
-23,500 total genomes
-BLAST: Basic Local Alignment Search Tool
-CLUSTAL: Global
-Global VS. Local alignment:
-Global: Try to arrange everything from beginning to end
-Local: Regions of high similarity, doesn‟t try to force two sequences to align together
(faster) *When is global weak and local is strong? Local similarities suggest similar functions
Reasons why amino acid sequence comparisons are more informative than
nucleotide sequence comparisons
-Much more info in amino acid sequence and much more powerful
-More information in an amino acid sequence of SAME LENGTH
-The genetic code is redundant
-You have 64 possible triplets but you only make 20 amino acids, one or more codon can specify
the same amino acid
-More noise in a nucleotide sequence, there‟s lots of stuff that doesn‟t really matter
-Amino acid sequence is much more highly conserved
-DNA databases are much larger
-DNA bases have lots of junk in it, which makes it hard to search
-Protein is much more specific & refined
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