Outline Mitosis and the Cell Cycle 1 Why

Outline: Mitosis and the Cell Cycle 1. Why we need cell division 2. Stages of the cell cycle 3. How bacteria are different 4. Regulating the cell cycle – how does a cell know when to go to the next stage? 5. Cancer – what happens when the cell cycle is unregulated

Fig. 12 -2 Cell division is important for: 100 µm (a) Reproduction 20 µm 200 µm (b) Growth and development (c) Tissue renewal

Cell division results in genetically identical daughter cells • Most cell division (mitosis) results in daughter cells with identical genetic information, DNA • A special type of division (meiosis) produces nonidentical daughter cells (gametes, or sperm and egg cells). These cells have half as much DNA as cells made by mitosis. Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Overview: Cell Division • 2 ways to divide the cell’s DNA: mitosis and meiosis Mitosis Meiosis Makes new somatic (body) cells Makes reproductive cells (eggs and sperm) Purpose: Growth, development, repair Purpose: Reproduction New daughter cells have the same number of chromosomes as the parent cell New daughter cells have half as many chromosomes as the parent cell “My toes are made by mitosis, my ova are made by meiosis. ” Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Organization of the Genetic Material • All the DNA in a cell constitutes the cell’s genome • A genome can consist of a single DNA molecule (common in prokaryotic cells) or a number of DNA molecules (common in eukaryotic cells) • DNA molecules in a cell are packaged into chromosomes, which are DNA molecules wrapped around proteins called histones. Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -3 20 µm

• Every eukaryotic species has a characteristic number of chromosomes in each cell nucleus • Somatic cells (nonreproductive cells) have two sets of chromosomes (1 from mom, 1 from dad) • Gametes (reproductive cells: sperm and eggs) have half as many chromosomes as somatic cells • Eukaryotic chromosomes are made condensed chromatin, a material made of DNA and protein Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Human Gamete Cell Chromosomes Human Somatic Cell Chromosomes Each chromosome is part of a pair of 2 homologous chromosomes Each chromosome is by itself – doesn’t have a homologous chromosome

Distribution of Chromosomes During Eukaryotic Cell Division • In preparation for cell division, DNA is replicated and the chromosomes condense • Each duplicated chromosome has two identical sister chromatids, which separate during cell division • The centromere is the narrow “waist” of the duplicated chromosome, where the two chromatids are most closely attached Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -UN 3

Fig. 12 -4 0. 5 µm Chromosomes Chromosome arm Centromere DNA molecules Chromosome duplication (including DNA synthesis) Sister chromatids Separation of sister chromatids Centromere Sister chromatids

• Eukaryotic cell division consists of: – Mitosis, the division of the nucleus – Cytokinesis, the division of the cytoplasm • Gametes are produced by a variation of cell division called meiosis • Meiosis yields nonidentical daughter cells that have only one set of chromosomes, half as many as the parent cell Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Outline: Mitosis and the Cell Cycle 1. Why we need cell division 2. Stages of the cell cycle 3. How bacteria are different 4. Regulating the cell cycle – how does a cell know when to go to the next stage? 5. Cancer – what happens when the cell cycle is unregulated

Phases of the Cell Cycle • The cell cycle consists of – Mitotic (M) phase (mitosis and cytokinesis) • Mitosis has 5 subphases – Interphase (cell growth and copying of chromosomes in preparation for cell division) • Interphase has 3 subphases Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

• Interphase (about 90% of the cell cycle) can be divided into subphases: – G 1 phase (“first gap”) – S phase (“synthesis”) – G 2 phase (“second gap”) • The cell grows during all three phases, but chromosomes are duplicated only during the S phase Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -5 S (DNA synthesis) G 1 is s e in G 2 M MIT (M) OTIC PHA SE ito Cy si s k o t G 1 + S + G 2 = Interphase M phase = Mitosis

• Mitosis is conventionally divided into five phases: – Prophase – Prometaphase – Metaphase – Anaphase – Telophase • Cytokinesis is well underway by late telophase Bio. Flix: Mitosis Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -UN 1 G 1 S Cytokinesis Mitosis G 2 MITOTIC (M) PHASE Prophase Telophase and Cytokinesis Prometaphase Anaphase Metaphase

Fig. 12 -6 a G 2 of Interphase Prometaphase

Fig. 12 -6 b G 2 of Interphase Chromatin Centrosomes (with centriole (duplicated) pairs) Prophase Early mitotic Aster spindle Nucleolus Nuclear Plasma envelope membrane Prometaphase Centromere Chromosome, consisting of two sister chromatids Fragments of nuclear envelope Kinetochore Nonkinetochore microtubules Kinetochore microtubule

The Mitotic Spindle: A Closer Look • The mitotic spindle is an apparatus of microtubules that controls chromosome movement during mitosis • During prophase, assembly of spindle microtubules begins in the centrosome, the microtubule organizing center • The centrosome replicates, forming two centrosomes that migrate to opposite ends of the cell, as spindle microtubules grow out from them Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

• An aster (a radial array of short microtubules) extends from each centrosome • The spindle includes the centrosomes, the spindle microtubules, and the asters Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

• During prometaphase, some spindle microtubules attach to the kinetochores (parts of the centromere that attach to the spindle fibers) of chromosomes and begin to move the chromosomes • At metaphase, the chromosomes are all lined up at the metaphase plate, the midway point between the spindle’s two poles Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -7 Aster Centrosome Sister chromatids Microtubules Chromosomes Metaphase plate Kinetochores Centrosome 1 µm Overlapping nonkinetochore microtubules Kinetochore microtubules 0. 5 µm

Fig. 12 -UN 4

Fig. 12 -6 c Metaphase Anaphase Telophase and Cytokinesis

Fig. 12 -6 d Metaphase Anaphase Metaphase plate Spindle Centrosome at one spindle pole Telophase and Cytokinesis Cleavage furrow Daughter chromosomes Nuclear envelope forming Nucleolus forming

• In anaphase, sister chromatids separate and move along the kinetochore microtubules toward opposite ends of the cell • The microtubules shorten by depolymerizing at their kinetochore ends Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

• Nonkinetochore microtubules from opposite poles overlap and push against each other, elongating the cell • In telophase, genetically identical daughter nuclei form at opposite ends of the cell Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Cytokinesis: A Closer Look • In animal cells, cytokinesis occurs by a process known as cleavage, forming a cleavage furrow • In plant cells, a cell plate forms during cytokinesis Animation: Cytokinesis Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -9 a 100 µm Cleavage furrow Contractile ring of microfilaments Daughter cells (a) Cleavage of an animal cell (SEM)

Fig. 12 -9 b Vesicles forming cell plate Wall of parent cell Cell plate 1 µm New cell wall Daughter cells (b) Cell plate formation in a plant cell (TEM)

Fig. 12 -10 a Nucleus Nucleolus 1 Prophase Chromatin condensing

Fig. 12 -10 b Chromosomes 2 Prometaphase

Fig. 12 -10 c 3 Metaphase

Fig. 12 -10 d 4 Anaphase

Fig. 12 -10 e Cell plate 5 Telophase 10 µm

Fig. 12 -UN 5

Outline: Mitosis and the Cell Cycle 1. Why we need cell division 2. Stages of the cell cycle 3. How bacteria are different 4. Regulating the cell cycle – how does a cell know when to go to the next stage? 5. Cancer – what happens when the cell cycle is unregulated

Binary Fission • Prokaryotes (bacteria and archaea) reproduce by a type of cell division called binary fission • In binary fission, the chromosome replicates (beginning at the origin of replication), and the two daughter chromosomes actively move apart Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -11 -1 Origin of replication E. coli cell Two copies of origin Cell wall Plasma membrane Bacterial chromosome

Fig. 12 -11 -2 Origin of replication E. coli cell Two copies of origin Origin Cell wall Plasma membrane Bacterial chromosome Origin

Fig. 12 -11 -3 Origin of replication E. coli cell Two copies of origin Origin Cell wall Plasma membrane Bacterial chromosome Origin

Fig. 12 -11 -4 Origin of replication E. coli cell Two copies of origin Origin Cell wall Plasma membrane Bacterial chromosome Origin

The Evolution of Mitosis • Since prokaryotes evolved before eukaryotes, mitosis probably evolved from binary fission • Certain protists exhibit types of cell division that seem intermediate between binary fission and mitosis Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -12 Bacterial chromosome (a) Bacteria Chromosomes Microtubules (b) Dinoflagellates Intact nuclear envelope Kinetochore microtubule Intact nuclear envelope (c) Diatoms and yeasts Kinetochore microtubule Fragments of nuclear envelope (d) Most eukaryotes

Outline: Mitosis and the Cell Cycle 1. Why we need cell division 2. Stages of the cell cycle 3. How bacteria are different 4. Regulating the cell cycle – how does a cell know when to go to the next stage? 5. Cancer – what happens when the cell cycle is unregulated

The eukaryotic cell cycle is regulated by a molecular control system • The frequency of cell division varies with the type of cell – some cells stop dividing altogether • These cell cycle differences result from regulation due to signaling molecules Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Evidence for Cytoplasmic Signals • The cell cycle appears to be driven by specific chemical signals present in the cytoplasm • We know this because if you put cytoplasm from one cell into a different cell, it can move that cell ahead in the cell cycle Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -13 EXPERIMENT Experiment 1 S G 1 Experiment 2 M G 1 RESULTS S S When a cell in the S phase was fused with a cell in G 1, the G 1 nucleus immediately entered the S phase—DNA was synthesized. M M When a cell in the M phase was fused with a cell in G 1, the G 1 nucleus immediately began mitosis—a spindle formed and chromatin condensed, even though the chromosome had not been duplicated.

The Cell Cycle Control System • The events of the cell cycle are directed by a cell cycle control system, which is similar to a clock • The cell cycle control system is regulated by internal and external controls • The clock has specific checkpoints where the cell cycle stops until a go-ahead signal (one of those molecules in the cytoplasm) is received Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -14 G 1 checkpoint Control system G 1 M G 2 M checkpoint G 2 checkpoint S

• For many cells, the G 1 checkpoint seems to be the most important one • If a cell receives a go-ahead signal at the G 1 checkpoint, it will usually complete the S, G 2, 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 G 0 phase Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -15 G 0 G 1 checkpoint G 1 (a) Cell receives a go-ahead signal G 1 (b) Cell does not receive a go-ahead signal

The Cell Cycle Clock: Cyclins and Cyclin-Dependent Kinases • Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases (Cdks) • The concentration of cyclins varies throughout the cell cycle • Cdks are dependent on cyclins, which activate them • When cyclin and Cdk bind together, they form the active molecule MPF that triggers a cell’s passage past the G 2 checkpoint into the M phase Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -16 5 30 4 20 3 2 10 1 0 100 200 300 Time (min) 400 0 500 % of dividing cells (– ) Protein kinase activity (– ) RESULTS

Fig. 12 -17 b 1 G Degraded cyclin M G 2 Cdk checkpoint Cyclin is degraded MPF Cyclin (b) Molecular mechanisms that help regulate the cell cycle Cyclin accumulation S Cdk

Stop and Go Signs: Internal and External Signals at the Checkpoints • Cyclins and cdks are proteins that can be made by ribosomes with instructions from DNA • You have genes in your DNA that give instructions for how to make these proteins • Gene expression is regulated – each gene can be turned on (causing that protein to be made) or off at different times • Internal and external signals lead to the genes for cyclins and cdks being turned on or off. Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Examples of signals • An example of an internal signal (comes from inside the cell) is that kinetochores not attached to spindle microtubules could send a molecular signal that delays anaphase • Some external signals (come from outside the cell) are growth factors, proteins released by certain cells that stimulate other cells to divide • For example, platelet-derived growth factor (PDGF) stimulates the division of human fibroblast cells in culture

Fig. 12 -18 Scalpels Petri plate Without PDGF cells fail to divide With PDGF cells proliferate Cultured fibroblasts 10 µm

Outline: Mitosis and the Cell Cycle 1. Why we need cell division 2. Stages of the cell cycle 3. How bacteria are different 4. Regulating the cell cycle – how does a cell know when to go to the next stage? 5. Cancer – what happens when the cell cycle is unregulated

• Another example of external signals is densitydependent inhibition, in which crowded cells stop dividing • Most animal cells also exhibit anchorage dependence, in which they must be attached to a stable surface in order to divide • Normal cells make a protein called p 53 to stop the cell cycle if there is a problem. In extreme cases, p 53 can cause a damaged cell to die (apoptosis) • Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence, and mutations in the gene for p 53 are the most common mutations leading to cancer Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -19 Anchorage dependence Density-dependent inhibition 25 µm (a) Normal mammalian cells (b) Cancer cells

Loss of Cell Cycle Controls in Cancer Cells • Cancer cells do not respond normally to the body’s control mechanisms; they grow and divide out of control • Cancer cells may not need growth factors to grow and divide: – They make their own growth factor – They may convey a growth factor’s signal without the presence of the growth factor – They may have an abnormal cell cycle control system Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

• A normal cell is converted to a cancerous cell by a process called transformation – Happens due to mutations that change the DNA, making the cell ignore regulatory checkpoints and measures. Mutations in p 53 are the most common. • Cancer cells form tumors, masses of abnormal cells within otherwise normal tissue • The lump is called a benign tumor if the cancer cells remain in the same place • Malignant tumors invade surrounding tissues and can metastasize, exporting cancer cells to other parts of the body, where they may form secondary tumors Copyright © 2008 Pearson Education, Inc. , publishing as Pearson Benjamin Cummings

Fig. 12 -20 Lymph vessel Tumor Blood vessel Cancer cell Metastatic tumor Glandular tissue 1 A tumor grows from a single cancer cell. 2 Cancer cells invade neighboring tissue. 3 Cancer cells spread to other parts of the body. 4 Cancer cells may survive and establish a new tumor in another part of the body.