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Genetics : Unit 1 Cell Cycle and Cancer
2012 – 2013
Chemical Constituents of Cells
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The human body is composed of ____________________ of cells
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Cells are constructed from numerous small molecules and _______________________________.
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These include ___________________________ (simple sugars and polysaccharides), amino acids and
_________________________, _________________ (fats and oils), and _____________________________
(nucleotides, DNA, RNA).
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______________________ are proteins that catalyze biochemical reactions that occur in the cell.
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________________________: set of proteins that a particular cell type can produce.
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Expression of _____________________________________________ in different cells (and therefore
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production of different proteomes) gives rise to over _____________ specialized cell types.
Organelles
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Organelles represent the ______________________________ in the cell and are involved in a variety of
functions
o The __________________ (storehouse of majority of DNA in the cell) has a double membrane and
nuclear pores, which allow macromolecular traffic in and out of the nucleus.
o The rough endoplasmic reticulum (ER), smooth ER, and Golgi body function as a
_______________________________________________ for the synthesis of proteins and lipids
 targeted for delivery to the _______________________________, organelles, or for
secretion
o Secretions bud off in _____________________ and leave cell
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A _____________________________________ has a double membrane whose inner folds carry enzymes that
catalyze reactions that extract energy from nutrients; also contains small amounts of DNA. (The
__________________________ in plant cells also contains a small amount of DNA)
________________________ contain enzymes that degrade cellular debris.
________________________ house enzymes that detoxify certain substances, break down lipids, and
synthesize bile acids.
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The Cell Cycle
• The cell cycle consists of _________________________, when a cell is not dividing, and _____________.
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______________________: of interphase: proteins, lipids, and carbohydrates are produced
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______________________: DNA and proteins are made
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______________________: more proteins are produced; replicated chromosomes have two sister
chromatids attached at their centromeres
• The cell cycle is tightly controlled and regulated at several "__________________________________“
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Non-dividing cells may become arrested during interphase and enter a quiescent phase
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_____________
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Replication of chromosomes
Replication is the process of
___________________________________________________
Occurs _____________________________________ in
_______________________ of the cell cycle
Replicated copies are called
_______________________________________
Held together at _________________________________
Control of Mitosis
• A cellular clock that limits the number of divisions is based on _____________________________________.
• Crowding, hormones, and growth factors are _________________________________________ on mitosis.
• Within cells, __________________ and _____________________ activate the genes whose products carry
out mitosis
Mitosis
• Purpose: to make _____________________________________________
• Replicated chromosomes align at the _______________________________ plate.
• _______________________________________________ separate and move to opposite poles
• Nuclear membranes form around each new ________________________.
• Division of cytoplasm or ________________________ occurs.
• Prophase
• Replicated chromosomes ___________________________________.
• Microtubules organize into a _____________________________
• Nuclear membrane ____________________________________
• ____________________________ split and move toward opposite poles of the cell
Metaphase
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• Chromosomes line up on the ___________________________________________.
• ________________________ microtubules are attached to centromeres of chromosomes.
Anaphase
• Centromeres of ____________________________________ separate
• Chromosomes ____________________to opposite ends of the cell
Telophase
• Chromosomes ____________________________ of cell, diffuse into ______________________________
• Nuclear membranes __________________________
• ___________________________ disappears
• Division of cytoplasm begins (____________________________________)
• Cytokinesis
• Cell ___________________________ in the middle and the two new cells separate
• Cytokinesis is part of the ______________________________ of the cell cycle, but usually considered
separate from mitosis; process begins during telophase and may continue after telophase is complete
Apoptosis
• Mitosis (cell division) and apoptosis (___________________________) are continuous processes that occur in
a series of steps and are both initiated by signals in the extracellular environment
• The balance between cell division and death ___________________________________ in growth,
development, and repair
• In prenatal development, coordination of these processes ______________________________________. After
birth, mitosis and apoptosis ________________________________ the body.
• Disruption of the balance between cell division and cell death can lead to _____________________ or other
disorders
• Programmed cell death is part of __________________ development
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Cancer
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Cancer is a group of diseases caused by _______________________________________________.
Cancer is associated with _______________________ uncontrolled cell growth.
_____________________________ are substances which cause cancer by mutating DNA.
Many genes that can _________________________to cause cancer control the cell cycle or DNA
maintenance (repair).
Origin of cancer
• Cancer begins from the growth of a ________________________________ cell.
• A mutation occurs allowing a cell to undergo cell division when it __________________________
normally divide.
• ______________________________ produces more abnormal cells.
• Mutations can occur:
• In _______________________ cells => sporadic cancer only affecting the individual
• In _______________________ cells => mutations that are inherited
• _______________________ mutations usually require second somatic mutation also.
Germline versus sporadic cancer
Telomeres affect the cell cycle
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________________________________ is the protein and enzyme complex that adds telomere sequences to
the ends of chromosomes.
Presence of telomerase and telomeres allows cells to pass a cell cycle _______________________ and divide.
• When telomerase is absent, _________________________________ are not added.
• Lack of telomeres signals ____________________________ of cell division.
Cancer can progress slowly over years
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Types of cancer genes
Type of gene
Tumor suppressor gene
Normal function
Promotes division
Mutated function
Promotes division abnormal time or cell type
Suppresses cell division
Fails to suppress division
DNA repair gene mutation
Fail to repair DNA
mutations
Types of proteins
Growth factors
Enzymes for mismatch or
excision repair
Characteristics of cancer cells
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Divide _________________________ (given space and nutrients)
_________________________________________: cells with mutations have daughter cells which inherit
the same mutations.
________________________: cells lose their specialized identity
___________________________________: reflects dedifferentiation
_____________________________________: will divide in a crowd of cells and pile on top of each other
Induce _________________________________ (local blood vessel formation)
Increased _________________________ rate
_____________________________: squeeze into any space available
_____________________________: cells move to new location in the body
Oncogenes
• _________________________________________ are normal versions of genes which promote cell division.
• Expression at the _________________________ or in the wrong cell type leads to cell division and cancer.
• Proto-oncogenes are called ___________________________ in their mutated form.
• ______________________________ of an oncogenic mutation is sufficient to promote cell division.
Tumor suppressor genes
• Cancer can be caused by loss of genes that ______________________ cell division.
• Tumor suppressor genes _________________________ stop a cell from dividing.
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• Mutations of ____________________ of a tumor suppressor gene is usually required to allow cell division.
p53 coordinates cell cycle regulation
• p53 acts as a cell cycle protein which determines if a cell has ____________________________________.
If damage cannot be repaired, p53 can induce ___________________________.
• More that ___________ of human cancers involve an abnormal p53 gene.
• Rare _____________________________ mutations in the p53 gene cause a disease called Li-Fraumeni
syndrome in which family members have many different types of cancer at early ages.
BRCA1, a breast cancer susceptibility gene
• Within families a mutation in BRCA1 leads to ______________________________ susceptibility, inherited
as a dominant trait.
• __________________ mutation in the BRCA1 gene is inherited.
• Tumors in people ______________________________________ mutation in the normal allele of BRCA1.
• Lack of any functional BRCA1 leads to ____________________ cells.
• At the level of the ______________, BRCA1 acts in a recessive manner.
Cancer treatments for breast cancer
Strategy
Examples
Remove cancerous tissue
Destroy cancerous tissue
________________________________________ to kill
dividing cells
Use phenotype to select drug
____________________ receptor positive women
take tamoxifen
Use _________________________ to select drug
Her-2/neu positive cancers targeted with herceptin
MAb
_________________________ level
Gene expression profile on DNA microarray to guide
drug choice
Environment impacts cancer
• Exposure to _______________________________
• Carcinogens in _________________________________ are correlated with lung cancer incidence.
• Exposure to _________________________
• Burns from overexposure to ______________________ can cause skin cancer.
• Variation in ______________
• Fatty diets are correlated with increased ______________________ and increased breast cancer.
Cruciferous vegetables can lower cancer risk
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Inside Cancer: Human Papilloma Virus
HPV: Introduction
 HPV comprises a group of small viruses with a double stranded DNA genome of about
__________________
 With ________________________ different types, HPV infects _______________________________ and
cause lesions ranging from external warts, cervical lesions, and cancer.
HPV: Low Risk and High Risk types
HPV’s are classified into low risk or high risk type:
1. Low-risk types _____________________ are mostly associated with genital warts, and only rarely associated
with cancer
2. High risk types _____________________ 31, 33, 35 are associated with cervical tumors (pre-cancer and
malignant):
HPV _____________ is the most prevalent type in both low grade and cervical tumors , with HPV 16 DNA found
in _______________ of cervical cancer.
HPV Evolutionary Groups
 HPV’s are contained within ___________________________________ groups:
Alpha, Beta, Gamma, Mu, and Nu.
 Alpha group contains HPV types that infect the _________________ and contains over 60 members.
 Beta, Gamma, Mu, and Nu primarily infect _______________
 90% of currently classified HPV’s belong to the __________________________________ group
How does HPV infect cells?
 HPV infects ____________________________________ of the epithelial lining. These are actively dividing
cells that will mature into squamous epithelial cells.
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HPV infection
 Infection occurs in the basal cell layer and results in the establishment of _________________________
that does not ___________________ into host DNA
 Stimulation of cell growth: is caused by HPV oncoproteins E6 and E7 which drive the cell into
__________________________.
 Basal cells normally _________________________________, but E6 and E7 viral proteins override the
normal cell cycle control in infected cells
HPV Productive vs Abortive Infection
Productive Infection
Abortive Infection
Tightly regulated gene expression
Viral gene expression is de-regulated
Results In
_______________________________
The ‘normal’ life cycle of the virus is no longer complete; no new virus
produced
Inactivation of major ___________________________________ proteins
Produces new infective viruses
abnormal cell division
Normal Squamous epithelium
 The _____________________________
show maturation from basal layer to
surface.
Abnormal Squamous Epithelium
 This is cervical squamous dysplasia at
high magnification extending from the
center to the right. The epithelium is
normal at the left. Note how the
dysplastic (abnormal) cell nuclei are
_______________________________,
and the dysplastic cells have a
disorderly arrangement.
Squamous cell carcinoma
 At high magnification, areas of
neoplastic (__________________)
squamous cells
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precursor to __________________
Tumor Suppressor Proteins
p53:
1) activates p21 ______________ inhibitor
progression
inhibits Cdk-cyclin
inhibits
2) ____________________________________
pRb
binds and inactivates transcription factor E2F
inhibits Cdk2CyclinE
inhibits ________________________ progression
HPV: Early and late gene expression
Viral Protein
Function
E1
E2
E4
E5
E6
E7
Initiation of DNA replication- viral genome amplification
Transcriptional regulation-viral genome amplification
Role in genome amplification not fully understood
Transmembrane protein found in the ER- involved in
EGF-mediated receptor signalling
Binds to and mediate p53 tumor suppressor protein
degradation, activates telomerase
Binds to and degrades pRB and mediates E2F
expression of cellular proteins required for S-phase
progression. Binds to and inactivates p21
L1
Formation of infectious virions
L2
Allows genome packaging to begin
Stages of HPV life cycle
Stage
Infection of basal cells:
Expression of viral proteins
Viral DNA transferred to nucleus by L2 capsid
1. Genome maintenance
E6/E7
2. Genome maintenance
Cell Proliferation (growth)
3. Genome Amplification
E6/E7
4. Virus Assembly
Virus release
pRB inactivation by E7 oncoprotein
Cytological Diagnosis of HPV lesions
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E6/E7
E6/E7
E1/E2/E4/E5
E1/E2/E4/E5
E1/E2/E4/E5
E4/L1/L2
cell cycle
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Cervical tumors are most often caused by HPV and characterized by the appearance of
___________________________________ cells with an ______________________________________
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CIN (cervical intra-epithelial neoplasia) is diagnosed by increasing severity:
 CIN 1- _____________________________________
 CIN 2- _____________________________________
 CIN 3- ________________- CIS ( carcinoma in-situ)
HPV statistics
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Approximately ______________________________ people are currently infected with genital human
papillomavirus (HPV) in the United States (U.S.).1
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Every year, about _____________________________ are diagnosed with cervical cancer, and almost
________ women die from this disease in the U.S.3 About ____________ of sexually active men and women
in the U.S. have genital warts at any given time.4
Prevalence of HPV infection among sexually active females
QuickStats: Prevalence of HPV* Infection† Among Sexually Active Females Aged 14--59 Years, by Age Group --National Health and Nutrition Examination Survey, United States, 2003--2004
Prevalence of high risk and low-risk types among females 14 to 59 years of age
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Figure 43. Human papillomavirus (HPV) — Prevalence of high-risk and low-risk types among females
_______________________ years of age reported from a national survey, 2003–2004
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Note: Error bars indicate _____________________________________. Both high-risk and low-risk HPV types
were detected in some females.
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SOURCE:
National Health and Nutrition Examination Survey JAMA, 2007, 297;813–819 Copyright © 2007, American
Medical Association. All Rights reserved.
HPV vaccine: Gardasil
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In June 2006 the FDA licensed Gardisil, the first vaccine developed to protect against genital warts and
_____________________________________________.
The vaccine has been widely tested in females ________________ around the world.
This _______________________________ vaccine works by preventing four HPV types: HPV
_______________, which cause ________________ of cervical cancers, and HPV
_________________________, which cause ________ of genital warts. The vaccine has no
___________________________________ on HPV-related disease.
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