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Western University Biochemistry 3385A Midterm Study Guide
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- University Of Western Ontario (UWO )
This is a full study guide for UWO's Biochemistry 3385A Midterm Exam.
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BIOCHEM3385 MIDTERM REVIEWTopic 1 Lecture 1: Cancer Key Concepts Pt. 1
Cancer: excessive cell proliferation, tumor forms
Usually benign but harmful if block organ function/hormone imbalance
Malignant tumors invade other areas
Causes of Cancer: lifestyle, genetics, and environment
Types of Cancer:
Epithelial Cells – carcinoma, squamous cell carcinoma, adenocarcinoma
Non-Epithelial Cells (connective tissue, neural cells, hematopoietic tissue) –
sarcoma, glioma/glioblastoma/neuroblastoma, leukemia/lymphoma
Tumorigenesis – tumor formation
Cells acquire many mutations (can be somatic/germline, genomic instability)
Tumors are monoclonal (comes from one cell)
Allows them to proliferate and escape apoptosis
Genes Involved in Cancer:
Oncogenes – normally regulate cell growth/survival (proto-oncogenes), loss of
cell control when hyperactive
Activation through overexpression, gene amplification, mutation that
keeps product active
Ex. Ras, Bcl-2
Tumor Suppressors – prevent over proliferation and induce apoptosis, loss of
cell control when deactivated
Deactivation through gene mutations (1 allele or 2 alleles), promoter
mutations, epigenetic events (ex. methylation)
Ex. p53 (transcription factor, also responds to cell cycle arrest, DNA
repair, apoptosis)
Ex. pRB (transcription factor, also regulates cell cycle)
6 “Hallmarks of Cancer” -malignant
Self-sufficient w/o growth signals
Doesn’t respond to anti-growth signals
Limitless replication
Evade apoptosis
Sustained angiogenesis
Tissue invasion/metastasis
Topic 1 Lecture 2: Cancer Key Concepts Pt. 2
Cell growth/proliferation regulated by signalling cascades, starting from extracellular
signals that bind to transmembrane receptors (ex. growth factors), leading to transcription
in nucleus
The RAS PATHWAY (start of signalling) - oncogene
o Growth factor/signal binds to membrane receptor (upstream stimulatory signal)
o Conformational change, next unit binds
Either Grb2, or Shc+Grb2
o This contains a GEF called Sos, removes GDP from Ras and allows GTP to bind
= active Ras (can induce the next pathway)
, The MAPK/ERK PATHWAY (activated by Ras) – kinase phosphorylation cascade
o Ras binds to Raf (kinase)
o Raf activates MEK (phos)
o MEK activates ERK (phos)
o ERK has many targets including nucleus (activates/alters transcription factors)
IN CANCER: mutation in Ras or Raf to make them hyperactive
The AKT/PKB PATHWAY (activated by Ras)
o Ras binds to PI3K (kinase), activated
o PI3K phos PIP3 (inositol lipid in membrane), activated
o PIP3 is docking site for AKT/PKB, activated (cell growth, anti-apoptotic)
PTEN is inhibitor (tumor suppressor), dephos PIP3 so AKT/PKB can’t
bind to it
IN CANCER: PI3K hyperactivation (either d/t mutation in Ras or PI3K),
PTEN deactivation (mutation – more common)
The Wnt-B-catenin Pathway (not activated by Ras) – stimulates gene transcription for
cell proliferation
o Complex containing APC, GSK-3B and B-catenin
Phosphorylates B-catenin, targets it for degradation
But with Wnt signal from membrane receptor, activates Dishevelled
inhibitor of APC complex
Complex cannot target B-catenin for degradation
B-catenin enters nucleus, activates transcription of genes
o FAP (familial adenomatous polyposis) – genetic cancer, many polyps
Mutation in APC gene, pathway always active w/o needing Wnt signal
Can also have mutations in p53 and Ras
The Invasion-Metastasis Cascade:
o Larger tumor = increased risk of metastasis
o Starts with primary tumor formation
Localized Invasion (out of basal membrane into stroma)
Intravasation (into blood/lymph)
Transport
Arrest in Various Organs (cells may become trapped; if not proceed to
general circulation)
Extravasation (out from vessels into tissue)
Colonization (in foreign tissue)
Familial Breast Cancer (genetic) – case of Shanna Larsen
o Mutations in BRCA1 and BRCA2 (involved in DNA repair)
Sporadic Breast Cancer
o Types based on histology, stage of cell transformation, tumor size/metastasis,
receptor status (what’s involved – HER2, estrogen/progesterone receptors or triple
negative)
o Prevention: genetic testing, vaccines (HepB, HPV)
o Diagnostic/Treatment: identify tumor markers and involved pathways
Topic 1 Lecture 3: The Cell Cycle
, Cell Cycle – duplication of cells = 2 identical daughter cells
o 4 stages:
G1(longest stage) – growth, transcription, etc
S – synthesis of new DNA
G2 – growth, transcription, etc.
M – mitosis + cytokinesis
Prophase, prometaphase, metaphase, anaphase, telophase,
cytokinesis
o Cycle checkpoints:
G1/S Checkpoint (most tightly regulated)
G2/M Checkpoint
Cell cycle regulated by Cdks (Cyclin-dependent kinases – phosphorylates), bind to
Cyclins
o Levels of Cyclin increase during mitosis (Cdk levels stay constant but need
Cyclin to activate)
Cyclin D = Cdk 4/6 – G1
Cyclin A + E = Cdk 2 – G1/S
Cyclin B = Cdk 1 – G2/M
Cyclin-Cdk Complex Regulation:
o Phosphorylation (dual – inhibitory + activating; dephos – remove inhibitory)
o Cdk Inhibitors (INK4 = Cyclin D + Cdk4/6, CIP/KIP = ANY complex)
o Degradation of Cyclins (ubiquitination = proteosome degradation)
The G1/S Transition (most tightly regulated)
o Growth factors/mitogens signal transcription of Cyclin D, forms complex with
Cdk 4/6
o Phosphorylates pRB (tumor suppressor/transcription factor) = released off of E2F
o Transcription of Cyclin A and E genes occurs, cycle proceeds to S phase
Positive Feedback Loop – Cyclin E/Cdk2 further phosphorylates pRB
Important to regulate b/c of Restriction (R) Point (committed to S phase,
no longer needs factors/mitogens)
o Regulation of Transition:
Positive: growth factors/mitogens, inhibit the Cdk inhibitors (INK4 – d/t
TGF-B)
Negative: withdrawal of factors/mitogens, cellular stress (ex. cell
adhesion)
The G1/S Checkpoint
o DNA damage signals for activation of p53 (tumor suppressor) by ATM kinase
o p53 activates transcription of CIP (broad Cdk inhibitor)
o CIP inhibits activity of Cyclin A/E + Cdk 2
The G2/M Checkpoint
o Cyclin B + Cdk 1 working here – increase activity of activating phosphatase
o DNA damage signals for activation of p53 by ATM kinase
ATM kinase also adds inhibitory phosphate onto activating phosphatase
o P53 activates transcription of CIP (broad)
o CIP inhibits activity of Cyclin B + Cdk 1
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