Regulation of Cell Division Frequency of cell division

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Regulation of Cell Division

Regulation of Cell Division

Frequency of cell division Ø Varies with cell type l Skin cells • Divide

Frequency of cell division Ø Varies with cell type l Skin cells • Divide frequently throughout life l Liver cells • Retain ability to divide l Mature nerve cells & muscle cells • Do not divide after maturity

Cell Cycle control Ø Two irreversible points in cell cycle l l Ø Replication

Cell Cycle control Ø Two irreversible points in cell cycle l l Ø Replication of genetic material Separation of sister chromatids Cell can be put on hold at specific checkpoints

Checkpoint control system Cell cycle controlled by STOP and GO chemical signals at critical

Checkpoint control system Cell cycle controlled by STOP and GO chemical signals at critical points Ø Signals indicate if key cellular processes have been completed correctly Ø 3 major checkpoints Ø

Ø G 1 l Can DNA synthesis begin? Ø G 2 l l Has

Ø G 1 l Can DNA synthesis begin? Ø G 2 l l Has DNA synthesis been completed correctly? Commitment to mitosis Ø M phases l l Spindle checkpoint Can sister chromatids separate correctly? Checkpoint Control System

G 1 Checkpoint Ø G 1 checkpoint is most critical l Primary decision point

G 1 Checkpoint Ø G 1 checkpoint is most critical l Primary decision point • “restriction point” l l If cell receives “go” signal, it divides If cell does not receive “go” signal, cell exits cycle & switches to Go phase • Non-dividing state

G 0 Phase Ø Non-dividing, differentiated state Ø Most human cells in Go l

G 0 Phase Ø Non-dividing, differentiated state Ø Most human cells in Go l phase Liver cells • In G 0, but can be “called back” to cell l Nerve & muscle cells • Highly specialized; arrested in G 0 & can never divide

Control of Cell Cycle

Control of Cell Cycle

Activation of Cell Division Ø How do cells know when to divide? l Cell

Activation of Cell Division Ø How do cells know when to divide? l Cell communication = signals • Chemical signals in cytoplasm give cue • Signals usually mean proteins l l Activators inhibitors

“Go-ahead” signals Ø Signals that promote cell growth & division l l Proteins Internal

“Go-ahead” signals Ø Signals that promote cell growth & division l l Proteins Internal signals • “promoting factors” l External signals • “growth factors” Ø Primary mechanism of control l Phosphorylation • Kinase enzymes

Protein signals – Promoting Factors Ø Cyclins l l Regulatory proteins Levels cycle in

Protein signals – Promoting Factors Ø Cyclins l l Regulatory proteins Levels cycle in the cell Ø Cdks l l l Cyclin-dependent kinases Enzyme activates cellular proteins MPF • Maturation (mitosis) promoting factor Ø APC l Anaphase promoting complex

Cyclins & Cdks (1970 s-80 s) Ø Interaction of Cdks & different cyclins triggers

Cyclins & Cdks (1970 s-80 s) Ø Interaction of Cdks & different cyclins triggers the stages of the cell cycle Leland H. Hartwell: checkpoints Sir Paul Nurse: cyclins Tim Hunt: Cdks

Cyclin & cyclin dependent kinases Ø CDKs & cyclin drive cell from one phase

Cyclin & cyclin dependent kinases Ø CDKs & cyclin drive cell from one phase to the next in the cell cycle l Genes for these regulatory proteins have been highly conserved through evolution • Proper regulation of cell cycle is key to life l These genes are basically the same in yeast, insects, plants, & animals

Ø Growth factors l Protein signals released by body cells that stimulate other cells

Ø Growth factors l Protein signals released by body cells that stimulate other cells to divide • Density-dependent inhibition l l Crowded cells stop dividing Mass of cells use up growth factors • Not enough left to trigger cell division • Anchorage dependence l To divide cells must be attached to a substrate External signals

Growth Factor Signals

Growth Factor Signals

Example of a Growth Factor: Platelet Derived Growth Factor Made by platelets Ø Binding

Example of a Growth Factor: Platelet Derived Growth Factor Made by platelets Ø Binding of PDGF to cell receptors stimulates fibroblast cell division Ø l Helps heal wounds

Growth Factors and Cancer Ø Proto-oncogenes l l Ø Normal genes that become oncogenes

Growth Factors and Cancer Ø Proto-oncogenes l l Ø Normal genes that become oncogenes (cancercausing) when mutated Stimulates cell growth If switched on cause cancer Ex. : RAS (activates cyclins) Tumor-suppressor genes l l l Inhibit cell division If switched off can cause cancer Ex. : p 53 – The cell cycle enforcer – discovered at Stony Brook by Dr. Arnold Levine

Cancer & Cell Growth Ø Cancer is essentially a failure of cell division control

Cancer & Cell Growth Ø Cancer is essentially a failure of cell division control l Ø Unrestrained, uncontrolled cell growth What control is lost? l l Checkpoint stops Gene p 53 plays a key role in G 1 checkpoint • p 53 protein halts cell division if it detects damaged DNA l l Stimulates repair enzymes to fix DNA Forces cell into G 0 resting stage Keeps cell in G 1 arrest Causes apoptosis of damaged cell • All cancers have to shut down p 53 activity

Development of Cancer Ø Cancer develops only after a cell experiences ~ 6 key

Development of Cancer Ø Cancer develops only after a cell experiences ~ 6 key mutations (“hits”) 1. Unlimited growth • 2. Ignore checkpoints • 3. Turn on chromosome maintenance genes Promotes blood vessel growth • 6. Turn off suicide genes Immortality = unlimited divisions • 5. Turn off tumor suppressor genes Escape apoptosis • 4. Turn on growth promoter genes Turn on blood vessel growth genes Overcome anchor & density dependence • Turn off censor gene

“Hits” can be triggered by… UV radiation Ø Chemical exposure Ø Radiation exposure Ø

“Hits” can be triggered by… UV radiation Ø Chemical exposure Ø Radiation exposure Ø Heat Ø Cigarette smoke Ø Pollution Ø Age Ø Genetics Ø

Tumors – mass of abnormal cells Ø Benign tumor l Abnormal cells remain at

Tumors – mass of abnormal cells Ø Benign tumor l Abnormal cells remain at original sit as a lump • P 53 has halted cell division l Most do not cause serious problems & can be removed by surgery Ø Malignant tumor l Cells leave original site • • • l Lose attachment to nearby cells Carried by blood & lymph system to other tissues Start more tumors = metastasis Impair functions of organs throughout body

Traditional treatments for cancer Ø Treatments target rapidly dividing cells l High energy radiation

Traditional treatments for cancer Ø Treatments target rapidly dividing cells l High energy radiation & chemotherapy with toxic drugs

New “Miracle Drugs” Ø Drugs targeting proteins (enzymes) found only in tumor cells l

New “Miracle Drugs” Ø Drugs targeting proteins (enzymes) found only in tumor cells l Gleevec • Treatment for adult leukemia & stomach cancer • 1 st successful targeted drug

Cancers = cell cycle genes Ø Cancer results from genetic changes that affect the

Cancers = cell cycle genes Ø Cancer results from genetic changes that affect the cell cycle l Proto-oncogenes • Normal cellular genes code for proteins that stimulate normal cell growth & division l Oncogenes • Mutations that alter proto-oncogenes cause them to become cancer-causing genes

Proto-oncogenes & oncogenes Ø Genetic change that can turn proto-oncogenes into oncogenes l Removing

Proto-oncogenes & oncogenes Ø Genetic change that can turn proto-oncogenes into oncogenes l Removing repression of genes

Cancers = failures of regulation Ø Cancer cells have escaped cell cycle controls l

Cancers = failures of regulation Ø Cancer cells have escaped cell cycle controls l Do not respond normally to the body’s control mechanisms • Divide excessively & invade other tissues • If unchecked, they can kill the organism

Effects of signal pathways

Effects of signal pathways

Multi-step model for cancer Ø Multiple mutations underlie the development of cancer l Several

Multi-step model for cancer Ø Multiple mutations underlie the development of cancer l Several changes must occur at DNA level for cell to become fully cancerous • Including at least 1 active oncogene & mutation or loss of several tumorsuppressor genes • Telomerase is often activated

p 53 gene Ø “Guardian of the Genome” l l The “anti-cancer gene” After

p 53 gene Ø “Guardian of the Genome” l l The “anti-cancer gene” After DNA damage is detected, p 53 initiates: • • • Ø DNA repair Growth arrest apoptosis Almost all cancers have mutations in p 53