CELL CYCLE

Muslima P. LiwalugMIB 1

OUTLINE: Cell Cycle Cell Regulation Oncogenes Apoptosis Characteristics of Cancer

CELL CYCLESimple Cell Cycle

o Cell division in bacteria takes places in 2 stages• DNA is copied• Cell splits (binary

fission)o Heredity in

bacteria encoded in single circle of DNA

Complex Cell Cycleo Eukaryotic DNA is

contained in linear chromosomes

• long DNA molecules packaged w/ proteins

o Mitosis - Mechanism of cell division occurring in non-reproductive (somatic) cells

o Meiosis - Mechanism of cell division occurring in reproductive (germ) cells

MITOSIS

A B

C D

MEIOSIS

PROPHASE 11. Leptotene• Pairing. Homologous dyads (pairs of

sister chromatids)• Thread-like chromatin with bead-like

chromomeres• Plants- chrom drawn in 1 side of nucleus

(synizesis)• Animals- drawn toward part of nuclear

membrane close to centriole

2. Zygotene• The synaptinemal complex begins to

form. • DNA strands of nonsister chromatids

begin recombination. 3. Pachytene• Synapsis is now complete. • Recombination The steps in

recombining DNA continue to the end of pachytene.

• Crossing over involves chromatid breaks and repairs

• Tetrad/bivalent formation occurs

4. Diplotene• DNA recombination is complete. • The synaptonemal complex begins

to break down. • Coiled nature of chrom very

apparent• The chromatids begin to pull apart ( terminalization) revealing

chiasmata.

5. Diakinesis• Chrom assume unique

configurations due to repulsion of chromatid pairs

• This is followed by the chromosomes recondensing in preparation for metaphase I.

• Bivalents bec distributed evenly in nucleus

• Nucleolus disintegrates and spindle fibers form

MITOSIS MEIOSIS

PARENT CELL(before chromosome replication)

Site ofcrossing over

MEIOSIS I

PROPHASE ITetrad formedby synapsis of homologous chromosomes

PROPHASE

Duplicatedchromosome(two sister chromatids)

METAPHASE

Chromosomereplication

Chromosomereplication

2n = 4

ANAPHASETELOPHASE

Chromosomes align at the metaphase plate

Tetradsalign at themetaphase plate

METAPHASE I

ANAPHASE ITELOPHASE I

Sister chromatidsseparate duringanaphase

Homologouschromosomesseparateduringanaphase I;sisterchromatids remain together

No further chromosomal replication; sister chromatids separate during anaphase II

2n 2n

Daughter cellsof mitosis

Daughter cells of meiosis II

MEIOSIS II

Daughtercells of

meiosis I

Haploidn = 2

n n n n

MITOSIS VS. MEIOSIS

Click icon to add picture

REGULATING

THECELL CYCLE

CELL CYCLE CHECK POINTSo Control loops that

make initiation of one event dependent on the successful completion of an earlier event

o Prevent damage that would ensue if cell were to undergo premature activity

CELL CYCLE CHECK POINTSo checkpoint for division

ensures that the previous mitosis is finished

o checkpoint for DNA integrity

ensures that all DNA is replicated and that there is no damage to it

o checkpoint for unreplicated DNA

ensures that all DNA is replicated and replicated only once

G1 checkpoint

M checkpoint G2 checkpoint

Controlsystem

Growth factor

Figure 8.8B

Cell cyclecontrolsystem

Plasma membrane

Receptorprotein

Signal transduction pathway

G1 checkpointRelayproteins

THE BINDING OF GROWTH FACTORS TO SPECIFIC RECEPTORS ON THE PLASMA MEMBRANE IS USUALLY NECESSARY FOR CELL DIVISION

Control Mechanisms for cell division

Apoptosis – programmed cell death

Schematic description of the controls in cell proliferation

Controlling the Cell Cycle• At critical points, further cell

progress depends on a central set of switches regulated by cell feedback.– G1 – Cell growth assessed– G2 DNA replication

assessed– M mitosis assessed

• Gene p53 plays a key role in G1 checkpoint of cell division.– Gene’s product monitors

integrity of DNA, checking for successful replication.

• If protein detects damaged DNA, it halts cell division and stimulates repair enzymes.

– Nonfunctional p53 genes allow cancer cells to repeatedly divide.

• Growth factors are proteins secreted by cells that stimulate other cells to divide

After forming a single layer, cells have stopped dividing.

Figure 8.8B

Providing an additional supply of growth factors stimulates further cell division.

Anchorage, cell density, and chemical growth factors affect cell division

In laboratory cultures, most normal cells divide only when attached to a surface– They are anchorage dependent

Cells anchor to dish surface and divide.

When cells have formed a complete single layer, they stop dividing (density-dependent inhibition).

If some cells are scraped away, the remaining cells divide to fill the dish with a single layer and then stop (density-dependent inhibition).

Cells continue dividing until they touch one another (Contact Inhibition)

Growth factors are proteins secreted by cells that stimulate other cells to divide

After forming a single layer, cells have stopped dividing.

Providing an additional supply of growth factors stimulates further cell division.

FACTORS THAT CONTROL CELL DIVISION

1. cellular clock• determines the number of times the cell divides• dependent on cell type• ex. Connective tissue cells- higher rate of division than adult cells

small intestine cells- divides during entire lifetime2. Cellular inhibition -Normal cells in culture grow in a monolayer -When expanding monolayer encounters a barrier, it will grow around not over it -When surface of culture dish is covered with cells growth stops -Expression of orderly and limited cell growth3. outside factors -hormones- cells lining uterus dependent on human progesteroneGrowth Factors 1. epidermal growth factor

whenever there is injury to epidermisgoverned by contact inhibitionalso present in saliva-animals lick wounds

2. Platelet-derived growth factor- first identified to induce cell to divide in culture

4.  intracellular factors -Early 1970s- subs + non-dividing cell - cell divides -Called it MPF- Maturation Promoting Factor -1988 (Lohka and Maller)- isolated MPF from Xenopus laevis -Induced cell to enter Mitosis (Called it M-Phase Promoting Factor)

Two Subunits of MPF 1. protein kinase-(p34 or cdc-2)o phosphorylates tyrosine and threonineo transfers phosphate groups from ATP to other proteins

that mediate cell cycle2. cyclin (p45)o -necessary for MPF to functiono -undergoes a cyclic of synthesis and degradationo -control progression through cell cycleo -defective cyclin results in uncontrolled cell division→

parathyroid tumor, breast cancer and leukemia

Cell cycle control

mechanisms

PREVENTING THE PROLIFERATION OF CANCER CELLS

Tumor suppressor genes like p53• Can arrest the cell cycle• Can launch the apoptotic pathway,

causing the rogue cells to lyseA mutation in the p53 gene can lead to

cancer

Immune cells (WBCs) such as NK cells can attack and lyse tumor cells• Some immune cells can signal the rogue

cells to launch the apoptotic pathways

CA

NC

ER

Genetic basis of cancer

Genetic disease at the cellular level caused by an accumulation of mutations over a lifetime

WHAT CAUSE TUMOR GROWTH

A. Proto-oncogenes proteins involved in growth and cell-cell interactionsB. Viruses contain ONCOGENES (gene that promotes cancer) Cancer genes which cause cell proliferation despite signal

saying ‘STOP’ many cancers have no viral association Insert into our chromosomes and transforms

• Epstein-Barr Virus --> Burkitt’s Lymphoma• Papillomaviruses --> cervical cancer

C. Tumor Suppressor Genes• Normal gene - prevents cells from dividing• when mutated - loss of function• cells divides out of control

D. Loss of a cell´s ability to undergo apoptosis

o Tumors (neoplasms) • new cells are being produced in greater

numbers than need• organization of the tissue becomes disrupted

o Transformation• Process of converting a normal cell into

malignant cell• rate of cell proliferation has increased

CHARACTERISTICS OF CANCER1. Clonal in origin – a hallmark of cancer cell

is that it divides to produce 2 daughter cells

2. Benign – non-invasive and precancerous genetic change

3. Malignant – when cells becomes cancerous and invasive to the neighboring cells

- becomes metastatic (they can migrate to other parts of the body and cause secondary tumors)

CANCEROUS CELLo Has large and multiple nucleio Irregular in shapeo Cells overlapping neighboring cells

o Loss of density – dependent or contact inhibition

o Loss of anchorage dependence

DISTINCTIVE APPEARANCE OF CANCER CELLS

CERTAIN VIRUSES CAN CAUSE CANCER BY CARRYING VIRAL ONCOGENES INTO THE CELL

o 15% of all human cancers are associated with viruseso Onco is incorporated into viral genome and this gene

can become a viral oncogene

Why does cancer occur when the gene is in viral genome?1. Many copies of the virus made during viral replication

may lead to overexpression of src gene2. The incorporation of the src gene next to viral

regulatory sequence may cause it to be overexpressed3. The v-src gene may accumulate additional mutations

that convert it to an oncogene

A GAIN-OF-FUNCTION MUTATION THAT PRODUCES AN ONCOGENE

1. The amount of the encoded protein is greatly increased

2. A change occurs in the structure of the encoded protein that causes it to be overly active

3. The encoded protein is expressed in a cell type where it is not normally expressed

GENETIC CHANGES IN PROTO-ONCOGENES CONVERT THEM TO ONCOGENES

1. Missense Mutation – changes of the structure of Ras protein can cause it to become permanently activated

2. Gene amplification – abnormal increase in the copy number of a proto-oncogene

3. Chromosomal translocation – translocation activates a proto-oncohgene

Philadelphia chromosome - shortened arm of chromosome # 22