KEY CONCEPT
Cells have dis2nct phases of growth, reproduc2on, and normal func2ons.
What is cell cycle?
• Cell cycle is defined as a period from
the end of one division to the
beginning of next division of a
prolifera<ve cell.
Your body cells go through a cycle too. This cycle allows new cells to be created to heal or replace dead or
damaged cells.
Cell division <ming
• Different cells have cell cycles of different lengths;
Cell type Cell cycle <me
Nerve Cells never Human Liver Cells 1 year
Red blood cell 4 months Skin cell 2 weeks Intes<nal epithelial cells 12 hours
Yeast cells 1.5 to 3 hours Bacteria 90 minutes
The cell cycle
• The cell cycle for prokaryo<c cells is a quick succession of growth, DNA replica<on, and cell division. Cell division in prokaryotes is a one-‐step
process called binary fission (shown right).
• Eukaryo<c cells have a more complex cell cycle than
How is the eukaryo<c
cell cycle divided?
• The <me between cell divisions is called interphase. The length of interphase varies depending on cell type.
• Eukaryo<c interphase is divided into three steps, or phases: G1, S, and G2.
• Eukaryo<c cells divide during the M phase of the cell cycle. The M phase consists of two steps:
Interphase
• The stage between two successive cell divisions (the ‘holding’ stage).
• Some 90 % of a cell's <me in the normal cell cycle may be spent in this phase
C = chroma<n I = nucleolus
Parts of Interphase
• G1 Phase
– Growing
– Synthesize new proteins and organelles
– Doing their jobs
– Longest phase of cell cycle
• S Phase
– Chromosomes(DNA) are replicated
– Key proteins associated with replica<on are made
(centromeres)
• G2 Phase
– Shortest of the 3 phases of interphase
– Organelles and molecules for cell division are produced (centrioles) – Check-‐up phase before mitosis
What happens during the M phase
of the eukaryo<c cell cycle?
• The M phase is usually much shorter than interphase and results in two daughter cells.
• The first step of the M phase is
mitosis. The cell’s nucleus
divides during mitosis.
• The second step of the M phase is cytokinesis, during which the cell’s cytoplasm is divided.
What are the steps of mitosis?
• Mitosis consists of four steps: Prophase
Metaphase Anaphase
Cytokinesis
-‐Cytoplasmic
division and other changes exclusive of nuclear division that are a part of mitosis or meiosis.
The Cell Cycle Control System
• The sequen<al events of the cell cycle are directed by a dis<nct cell cycle control system, which is
similar to a clock
• The clock has specific checkpoints where the cell cycle stops un<l a go-‐ahead signal is received
Defini<on of Checkpoint
n Cell cycle is a highly ordered process: the
ini<a<on of later event depends on the comple<on of earlier events.
n The control mechanisms that enforce this
ordered dependency are called cell cycle checkpoint.
G1 checkpoint G1 S M M checkpoint G2 checkpoint G2 Control system
24
Control of the Cell Cycle
The cell cycle is controlled at three checkpoints: 1. G1/S checkpoint
-‐the cell “decides” to divide 2. G2/M checkpoint
-‐the cell makes a commitment to mitosis 3. late metaphase (spindle) checkpoint
-‐the cell ensures that all chromosomes are ahached to the spindle
Regula<on of the Cell Cycle:
Cell Cycle Checkpoints
E.g. Oocytes
Differentiating cells
• can sister chroma<ds separate correctly?
• has DNA synthesis been completed correctly?
• commitment to mitosis
• For many cells, the G1 checkpoint seems to be the most important one
• If a cell receives a go-‐ahead signal at the G1 checkpoint, it will usually complete the S, G2, and M phases and divide
• If the cell does not receive the go-‐ahead signal, it will exit the cycle, switching into a nondividing state called the G0 phase
LE 12-‐15
G1 G1 checkpoint
G1 G0
If a cell receives a go-‐ahead signal at the G1 checkpoint, the cell con2nues on in the cell cycle.
If a cell does not receive a go-‐ ahead signal at the G1
checkpoint, the cell exits the cell cycle and goes into G0, a
Stop and Go Signs: Internal and External
Signals at the Checkpoints
• An example of an internal signal is that
kinetochores not ahached to spindle microtubules send a molecular signal that delays anaphase
• Some external signals are growth factors, proteins released by certain cells that s<mulate other cells to divide
• For example, platelet-‐derived growth factor (PDGF) s<mulates the division of human fibroblast cells in culture
How do cells know when to divide and
when not to?
• Internal regulators – are proteins that respond to events inside the cell.
– Some proteins make sure cells do not enter
mitosis un<l all of the chromosomes have been replicated.
• Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-‐dependent kinases (Cdks)
• The ac<vity of cyclins and Cdks fluctuates during the cell cycle
LE 12-‐14 G1 checkpoint G1 S M M checkpoint G2 checkpoint G2 Control system
Proteins within the cell control the cell cycle
Signals affecting critical checkpoints determine whether the cell will divide (cyclins, kinases)
32
Control of the Cell Cycle
At G1/S checkpoint:
-‐ G1 cyclins accumulate
-‐ G1 cyclins bind with Cdc2 to create the ac<ve G1/S Cdk
-‐ G1/S Cdk phosphorylates a number of molecules that ul<mately increase the enzymes required for DNA replica<on
LE 12-‐16b Degraded cyclin G 2 checkpoint Cdk Cyclin is degraded MPF Cyclin Cdk
Molecular mechanisms that help regulate the cell cycle ac cum ula2 on Cy cl in
LE 12-‐16a MPF ac2vity G1 S G2 M S G2 M G1 M Cyclin Time
Fluctua2on of MPF ac2vity and cyclin concentra2on during the cell cycle
Rela 2v e co ncen tr a2on
External Factors that can Influence
Cell Division
1. Chemical factors-
a. Lack of nutrients inhibit cell division
b. Presence of specific growth
factors are needed for cell division
– Platelet-derived Growth Factor
(PDGF) is required for division of fibroblasts used in healing
– Receptors on plasma membrane
bind PDGF and trigger pathway to signal cell division
2. Physical factors-
a. Density-dependent inhibition
• Cell division limited by quantities of nutrients and growth regulators
b. Anchorage-dependent inhibition • Cells must attach to substratum
(surface)
• Anchorage is signaled to cell-cycle control system by linkage between membrane proteins and elements of cytoskeleton
External Regulators
• External regulators -‐ Proteins that respond to events outside the cell are called external regulators.
• External regulators direct cells to speed up or slow down the cell cycle.
• Growth factors are among the most important external regulators, which tell cells to speed up division. When is this important?
• Molecules found on the surfaces of neighboring cells omen have an opposite effect, causing cells to slow down or stop their cell cycles.
External Signals
Cells anchor to dish surface and divide (anchorage dependence). When cells have formed a complete single layer, they stop dividing
(density-‐dependent inhibi2on).
If some cells are scraped away, the
remaining cells divide to fill the gap and then stop (density-‐dependent inhibi2on).
25 µm Normal mammalian cells
•
Mitosis occurs only if:
–
the cell is large enough
–
and the DNA is undamaged
•
If the DNA is damaged, the cell
commits suicide – so it doesn’t
pass on bad DNA
How DNA
damage
arrests the
Control of Cell Cycle
What happens when checkpoints fail? Cancer can occur
Cancer Cells have Escaped Cell-cycle
Control
Cancer cells do not respond normally to the body’s control mechanisms and divide excessively
1. Density-independent—make their own growth factors and continue to divide uncontrolled (“immortal”)
LE 12-‐18a
Cells anchor to dish surface and divide (anchorage dependence).
When cells have formed a complete single layer, they stop dividing
(density-‐dependent inhibi2on).
If some cells are scraped away, the
remaining cells divide to fill the gap and then stop (density-‐dependent inhibi2on).
25 µm Normal mammalian cells
LE 12-‐18b
Cancer cells do not exhibit anchorage dependence
or density-‐dependent inhibi2on.
Cancer cells
Loss of Cell Cycle Controls in Cancer Cells
• Cancer cells do not respond normally to the body’s control mechanisms
• Cancer cells form tumors, masses of abnormal cells within otherwise normal <ssue
• If abnormal cells remain at the original site, the lump is called a benign tumor
• Malignant tumors invade surrounding <ssues and can metastasize, expor<ng cancer cells to other parts of the body, where they may form secondary tumors
Abnormal cells that escape cell-cycle control are products of mutated or transformed normal cells
1. May proliferate to form a tumor—an unregulated growing mass of cells within normal tissue
• Benign tumor—if cells remain at the original site • Malignant tumor—if mass impairs normal
function of one or more organs of the body » Excessive proliferation
» Cells with unusual number of chromosomes » Aberrant metabolism
» Detaches and migrates through body (metastasis)
Growth control in a normal cell
Signaling cell
Growth factor =
Growth factor binds to receptor Receptor sets off
a signal cascade to
nucleus
target cell enters S-phase and divides, eventually repairing wound target cell Nucleus
1. Cell might produce its own growth factor
Several ways to get faulty growth control in a cancer cell 2. Mutant receptor might turn on even without
binding growth factor 3. Signal cascade might occur even without trigger
53
What causes Cancer?
• Cancer is caused by
alterations or mutations in the genetic code
• Can be induced in somatic cells by: – Carcinogenic chemicals – Radiation – Some viruses • Heredity - 5%
55
• What is the molecular basis of cancer?
• Cancer is a gene<c disease.
• Muta<ons in genes result in altered proteins – During cell division
– External agents – Random event
• Most cancers result from muta<ons in soma<c cells
• Some cancers are caused by muta<ons in germline cells
56
What are the genes responsible for tumorigenic cell growth?
Normal
Cancer
Proto-oncogenes Cell growth
and proliferation Tumor suppressor genes
+
-Mutated or activated oncogenes Malignant transformation Loss or mutation of
Tumor suppressor genes
• Characteristics of Cancer Cells
• Cancer cells lack differentiation.
• Cancer cells have abnormal nuclei.
• Cancer cells form tumors.
• Cancer cells undergo metastasis and
angiogenesis.
• Unlike normal cells that differentiate into muscle or nerves cells, cancer cells have an abnormal form and are nonspecialized.
• Normal cells enter the cell cycle only about 50 times; cancer cells are immortal in that they can enter the cell cycle repeatedly.
• The nuclei may be enlarged and may have an abnormal number of chromosomes.
• The chromosomes have mutated; some chromosomes may be duplicated or deleted.
• Gene amplification, extra copies of genes, is more frequent in cancerous cells.
• Whereas ordinary cells with DNA damage undergo apoptosis, cancer cells do not.
• Normal cells are anchored and stop dividing when in contact with other cells; i.e., they
exhibit contact inhibition.
• Cancer cells invade and destroy normal tissue and their growth is not inhibited.
• Cancer cells pile on top of each other to form a tumor.
• A benign tumor is encapsulated and does not invade adjacent tissue.
• Cancer in situ is a tumor in its place of origin but is not encapsulated—it will invade surrounding tissues.
• Many types of cancer can undergo metastasis, in which new tumors form which are distant from the primary tumor.
• Angiogenesis, the formation of new blood vessels, is required to bring nutrients and oxygen to the tumor.
• A cancer patient’s prognosis depends on whether the tumor has invaded surrounding tissue, whether there is lymph node involvement, and whether there are metastatic tumors
elsewhere in the body.
LE 12-‐19 Cancer cell Blood vessel Lymph vessel Tumor Glandular 2ssue Metasta2c tumor A tumor grows from a
single cancer cell. Cancer cells invade neighboring 2ssue. Cancer cells spread through lymph and blood vessels to other parts of the body.
A small percentage of cancer cells may survive and establish a new tumor in another part of the body.
Cancer treatment:
Attack Actively Dividing Cells
• Three treatments for cancer:
1. Surgery 2. Radiation
Phase-specific Chemotherapies 1. Prevent cells from entering the S-phase
2. Block the S phase
Phase Specificity of Cytotoxic Drugs
Phase of cell cyle Effective agents
G1 Steroids, asparaginase
S phase Antimetabolites
G2 Bleomycin, etoposide
Mitosis Vinca alkaloids, taxanes
Phase non-specific Alkylating agents,
nitrosoureas, antibiotics, procarbazine, dacarbazine, platinums
But chemotherapy can’t discriminate between cancer cells and normal cells….
• May affect all rapidly dividing cells • Which cells divide rapidly?
Chemotherapy Side Effects
• Chemotherapy targets cells which are dividing rapidly.
• Chemotherapy cannot dis<nguish between normal cells and cancer cells
• Healthy Cells which have a high rate of growth and mul<plica<on include cells of the bone
