Control of cell growth

Cells in a multicellular organism communicate through chemical signals Hormones act over a long rangeLocal mediators are secreted into the local environmentSome cells communicate through direct cell-cell contact

• Cells are stimulated when extra cellular signalling molecules bind to a receptor

• Each receptor recognises a specific protein (ligand)

• Receptors act as transducers that convert the signal from one physical form to another.

The cell cycle• The eukaryotic cell cycle consists of

distinct phases• The most dramatic events are nuclear

division (mitosis) and cytoplasmic division (cytokinesis)

• This is the M phase• The rest of the cell cycle is called

interphase which is, deceptively, uneventful

• During interphase the cell replicates its DNA, transcribes genes, synthesises proteins and grows in mass

Phases of the cell cycle

• S phase – DNA replicates• M phase – nucleus divides

(mitosis) and cytoplasm divides (cytokinesis)

• G1 phase – gap between M and S phase

• G2 phase – between S and M phase

Cell cycle control• Cell cycle machinery is subordinate to a cell cycle control

system• The control system consists mainly of protein complexes• These complexes consist of a cyclin subunit and a Cdk

subunit• The cyclin has regulatory function, the Cdk catalytic

function• Cdk expression is constant, but cyclin concentrations rise

and fall at specific times in the cell cycle• The Cdks are cyclically activated by cyclin binding and by

phosphorylation status• Once activated, Cdks phosphorylate key proteins in the

cell

• Different cyclin-Cdk complexes trigger different cell cycle steps

• Some drive the cell into M phase, others into S phase• The cell cycle control system has in-built molecular

breaks (checkpoints)• The checkpoints ensure that the next step does not

begin until the previous one is complete

MPF (“maturation-promoting factor” or “M-phase-promoting-factor”) triggers the cell’s passage past the G2 checkpoint to the M phase.MPF promotes mitosis by phosphorylating a variety of other protein kinases.MPF stimulates fragmentation of the nuclear envelope.It also triggers the breakdown of cyclin, dropping cyclin and MPF levels during mitosis and inactivating MPF.The key G1 checkpoint is regulated by at least three Cdk proteins and several cyclins.Similar mechanisms are also involved in driving the cell cycle past the M phase checkpoint.

controls the passage of eukaryotic cells from the first 'gap' phase (G1) into the DNA synthesis phase (S).

Checks:

That the size is CORRECT

That the environment is CORRECT

G1/S cell cycle checkpoint

Three checkpoints:

The G1/S cell cycle checkpoint

G2/M DNA damage checkpoint

Mitosis checkpoint

G1/S cell cycle checkpointHow do they do that?

Major proteins involved:

Cyclins (proteins) - level fluctuate in the cell cycle.

&

Cyclin dependent KINASES* (Cdks)

They add phosphate groups to proteins that control processes in the cell cycle.

They only do this when the cyclins are present.

The G1 checkpoint• The G1 checkpoint has

been widely studied• The retinoblastoma (Rb)

protein plays a key role at this checkpoint

• The Rb protein function is determined by its phosphorylation status

• S phase cyclin-Cdk complexes phosphorylate Rb

The G1 checkpoint

• This checkpoint is influenced by the action of cyclin-dependant kinase inhibitors (CKIs, e.g. p21, p16)

• E.g. p53 senses DNA damage and induces p21 expression

• CKIs inactivate cyclin-Cdk complexes

G2/M DNA damage checkpoint

The G2/M DNA damage checkpoint prevents the cell from entering mitosis (M phase) if the genome is damaged.

It also checks if the cell is big enough (i.e. has the resources to undergo mitosis)

Almost exclusively, internally controlled

M checkpoint

The M checkpoint is where the attachment of the spindle fibres to the centromeres is assessed.

Only if this is correct can mitosis proceed.

Failure to attach spindle fibres correctly would lead to failure to separate chromosomes

Cellular adaptations of growth and differentiation

• Cells must respond to a variety of stimuli that may be hormonal, paracrine or through direct cell contact

• These stimuli may arise under physiological or pathological conditions

• The way that cells adapt in terms of growth and differentiation depends in part on their ability to divide

Cellular proliferative capacity

• Tissues can be classified according to the ability of their cells to divide

• Some tissues contain a pool of cells that move rapidly from one cell cycle to the next. These are labile cells

• Some cells dismantle their cell cycle control machinery and exit the cell cycle

• These cells are said to be in G0.

• Some of these cells can re-enter the cell cycle when stimulated, e.g. by growth factors. These are stable cells

• Others are unable to re-enter the cell cycle. These are permanent cells

Growth and differentiation responses

1- Hyperplasia2- Hypertrophy3- Atrophy4- Metaplasia

1- Hyperplasia:• Increase in the number of cells in an organ or

tissue, which may then have an increased size

2- Hypertrophy:• An increase in cell size, and resultant increase in

organ size

3- Atrophy:• Shrinkage in cell size by loss of cell substance

4- Metaplasia:

• Reversible change of one adult cell type to another adult cell type

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• The continuity of life from one cell to another is based on the reproduction of cells via cell division.

• This division process occurs as part of the cell cycle (the life of a cell from its origin in the division of a parent cell until its own division into two).

• The division of a unicellular الخلية organism وحيد(e.g. Amoeba) reproduces an entire organism, increasing the population.

• Cell division is also central to the development of a multicellular الخلية organism that begins as a عديدfertilized egg or zygote.

Introduction

Fig. 12.1, Page 216

Figs. 12.1, Page 216

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Division is differ among cells:.

- Skin cells divide frequently.

- Liver cells divide when needed (damage repair).

- Nerve cells and muscle cells do not divide at all.

Figs. 12.1, Page 216

Multicellular organisms also use cell division to repair and renew cells that die normally or by accidents (blood cells from bone marrow).

Cell division distributes the genetic material (DNA) to two daughter cells.

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• A cell’s genetic information (genome الـ ينىچالبنك ) is packaged as DNA.• In prokaryotes, the genome is often a single long DNA molecule.

– In eukaryotes, the genome consists of several DNA molecules.• A human cell must duplicate about 3 m of DNA and separate the two copies

such that each daughter cell ends up with a complete genome.• DNA molecules are packaged into chromosomes.

– Every eukaryotic species has a characteristic number of chromosomes in the nucleus.

– Human somatic cells (body cells) have 46 chromosomes.

– Human gametes أمشاج (sperm or eggs) have 23 chromosomes, half the number in a somatic cell الجسدية .الخلية

• Each eukaryotic chromosome consists of a long, linear DNA molecule.

Cell division distributes identical sets of chromosomes to daughter cells

Fig. 12.2, Page 216

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• Each chromosome has hundreds or thousands of genes (the units that specify an organism’s inherited characters الوراثية .(الصفات

• This DNA-protein complex (chromatin) is organized into a long thin fiber.• After the DNA duplication, chromatin condenses form

(chromosome).

• Each duplicated chromosome consists of two sister chromatids which contain identical copies of the chromosome’s DNA.

• The narrow region where the chromosomal strands connect is the called centromere.

• Later, the sister chromatids are pulled apart and repackaged into two new nuclei at opposite ends of the parent cell during cell division.

• The process of the formation of the two daughter nuclei called (mitosis) and is usually followed by division of the cytoplasm (cytokinesis الخلوى اإلنشطار ). It occurs in somatic cells الجسدية الخاليا

Fig. 12.3, Page 217

22

ChromatidChromatin +

DNA

Sister chromatid

Chromosome الصبغ

Centromere

Homologous Chromosome

23

• In the gonads المناسل, cells undergo a meiosis division, which yields four daughter cells, each with half the chromosomes number of the parent cell.– In humans, meiosis reduces the number of chromosomes from 46 to 23.

• Each of us inherited 23 chromosomes from each parent: one set in an egg and one set in a sperm during meiosis.

• gametes األمشاج(eggs or sperm) are produced only in gonads المناسل (ovaries or testes).

• The fertilized egg undergoes trillions of cycles of mitosis and cytokinesis to produce a fully developed multicellular human.

• These processes continue every day to replace dead and damaged cell.

• Fertilization fuses two gametes together and doubles the number of chromosomes to 46 again.

24

Genes: The units that specify an organism’s inherited characters.

Chromatin: A DNA-protein complex which is organized into a long thin fiber

Chromosome: The package that formed from a condensed, coiled and folded chromatin.

Chromatids: Two sister arms (chromatids) formed from each duplicated chromosome. They contain identical copies of the chromosome’s DNA

Centromere: The narrow region at which the chromosomal strands are connect together.

Mitosis: Is the division process which forms two daughter nuclei

Cytokinesis: الخلوى اإلنشطار Is the division stage of the cytoplasm which usually follow the mitosis.

Definitions

Meiosis: A division process that occurs In the gonads المناسل, and yields four daughter cells, each with half the chromosomes of the parent.

25

A. Mitosis: is usually include five sub-phases فرعية :مراحل Prophase, التمهيدية Prometaphase, اإلستوائية قبل Metaphase, اإلستوائية Anaphase, اإلنفصالية Telophase. اإلنتهائية

• By late interphase (G2), the chromosomes have been duplicated تضاعفت but are loosely packed.

• The centrosomes have been duplicated and begin to organize microtubules into an aster (“star”).

Fig. 12.5a, 218

26

1) Prophase, التمهيدية the chromosomes are tightly coiled, with sister chromatids joined together, The nucleoli disappear. The mitotic spindle begins to form and appears to push the centrosomes away from each other towards opposite ends (poles) of the cell.

2) Prometaphase, اإلستوائية the nuclear قبلenvelope fragments and microtubules from one pole attach to one of two kinetochores (special regions of the centromere) while microtubules from the other pole attach to the other kinetochore.

3) Metaphase, اإلستوائية the spindle fibers push the sister chromatids until they are all arranged at the imaginary plane equidistant between the poles, defining metaphase.

Fig. 12.5b, C & D, Page 218-219

27

• Anaphase, اإلنفصالية the centromeres divide, result in separating the sister chromatids. Each is then pulled toward the pole to which it is attached by spindle fibers. By the end, the two poles have equivalent collections of chromosomes.

• Telophase, اإلنتهائية the cell continues to elongate as free spindle fibers from each centrosome push off each other.

1) Two nuclei begin to form, surrounded by the fragments of the parent’s nuclear envelope.

2) Chromatin becomes less tightly coiled.3) Cytokinesis, begins as the division of the

cytoplasm occurs.

Fig. 12.5e & f, Page 219

28Fig. 12.5 left

29Fig. 12.5 right

30

• Cytokinesis (division of the cytoplasm) typically follows mitosis.

• Contraction إنقباض of the cell pinches the cell into two new cells

B. The cytokinesis: الخلوى اإلنشطار divides the cytoplasm:

Fig. 12.8, Page 222

31Fig. 12.9, Page 223

32

Cell Cycle

Interphase

Prophase التمهيدية

Prometaphase اإلستوائية قبل

Metaphase اإلستوائية

Anaphase اإلنفصالية

Telophase اإلنتهائية

G1 S G2

Division process

Mitosis Cytokinesis

33

A life cycle of an organism is the generation-to-generation sequence of stages in its reproductive history.

It starts at the conception of an organism until it produces its own offspring .نسل

In humans, each somatic cell (all cells other than sperm or ovum) has 46 chromosomes.

These homologous chromosome المتم لةاثالكروموسومات pairs carry genes that control the same inherited characters.

A karyotype الكروموسومى display of the 46 chromosomes shows 23 الطرزpairs of chromosomes, each pair with the same length, centromere position, and staining pattern.

Fertilization and meiosis alternate يتعاقبا in sexual life cycles

34

The Karyotype الكروموسومى :الطرز

It is a display of an individual’s chromosomes that arranged according to size and shapes)

Fig. 13.3, Page 237

35

• An exception to the rule of homologous chromosomes is found in the sex chromosomes, the X and the Y.

• The pattern of inheritance of these chromosomes determine an individual’s sex الفرد جنس .نوع– Human females have a homologous pair of X chromosomes (XX).– Human males have an X and a Y chromosome (XY).

• The other 22 pairs are called autosomes الذاتية .الكروموسومات

• We inherit one chromosome of each homologous pair المتماثلة from األزواجeach parent.– The 46 chromosomes in a somatic cell can be viewed as two sets of 23, a

maternal set األم األب and a paternal set مجموعة . مجموعة

• Sperm cells or ova (gametes) have only one set of chromosomes - 22 autosomes and an X or a Y.

• A cell with a single chromosome set is haploid فردى.– For humans, the haploid number of chromosomes is 23 (n = 23).

Chromosomes (sex and autosomes)

36

• A haploid sperm reaches and fuses يندمج with a haploid ovum.

• These cells fuse (syngamy اإلزدواج) resulting in fertilization.

• The fertilized egg (zygote) now has a diploid زوجى set of chromosomes from the maternal and paternal family lines.

• The zygote and all cells with two sets of chromosomes are diploid cells زوجى46 (2n = 46).

• As an organism develops from a zygote to a sexually mature adult, the zygote’s genes are passes on to all somatic cells by mitosis.

• Gametes, which develop in the gonads, are not produced by mitosis.

• Instead, gametes undergo the process of meiosis in which the chromosome number is halved للنصف mختزل .ي– Human sperm or ova have a haploid set of 23 different chromosomes, one from

each homologous pair.

37Fig. 13.4, Page 238

Gametes, produced by meiosis, are the only haploid cells.

Gametes undergo no divisions themselves, but fuse تندمج to form a diploid zygote that divides by mitosis to produce a multicellular organism

• Fertilization restores عيدm sets فردى condition by combining two haploid زوجى the diploid يof chromosomes.

• Fertilization and meiosis alternate in sexual life cycles.

38

Many steps of meiosis resemble steps in mitosis. Both are preceded by the replication of

chromosomes. However, in meiosis, chromosomes replicate once

followed by two consecutive متعاقب cell divisions, meiosis I and meiosis II, which results in four daughter cells.

Each final daughter cell has only half chromosomes number (haploid (فردى.

Meiosis reduces chromosome number by copying the chromosomes once, but dividing twice. The first division (meiosis I) separates homologous

chromosomes. The second (meiosis II) separates sister chromatids.

Meiosis (Reduction Division) اإلختزالى اإلنقسامReduces chromosome number from diploid to haploid :

39

2- Meiosis Division (Reduction Division)

A)- Meiosis I B)- Meiosis II

- Separate homologous chromosomes.

- Results in 2 haploid cells with replicated chromosomes.

- Separate homologous chromosomes.

- Results in 2 haploid cells with replicated chromosomes.

- No further replication of chromosomes.-Occurs in the newly resulting cells from Meiosis I.

(4 haploid cells)

- No further replication of chromosomes.-Occurs in the newly resulting cells from Meiosis I.

(4 haploid cells)

It occurs mainly in sex gonads to form Gametes (sperms and ova)

Each of the resulting cells has half number of chromosomes of the original cell (23 in human). Thus, it called Reduction Division

Occurs in two steps

40

Fig. 13.7

1)- interphase the chromosomes are replicated to form sister chromatids.

MeiosisA)- Meiosis I: is very similar to mitosis.

2)- Prophase I, the chromosomes condense and homologous chromosomes pair up تزدوج to form tetrads مجموعات .رباعية

• Homologous chromosomes attached together (synapsis .(التشابك– Chromatids of homologous chromosomes are crossed (at

chiasmata) and segments of the chromosomes are exchanged (Crossing Over).

41

2)- Metaphase I, the tetrads are all arranged at the metaphase plate.– Microtubules from one pole are attached to the kinetochore of one chromosome of

each tetrad, while those from the other pole are attached to the other.

3)- Anaphase I, the homologous chromosomes separate and are pulled toward opposite poles.

Fig. 13.7

42

5)- Telophase I, movement of homologous chromosomes continues until there is a haploid set at each pole.– Each chromosome consists of linked sister

chromatids.

• Cytokinesis by the same mechanisms as mitosis usually occurs simultaneously.

• In some species, nuclei may reform, but there is no further replication of chromosomes.

Fig. 13.7

43

B)- Meiosis II 1)- Prophase II a spindle apparatus forms, attaches to kinetochores of each sister chromatids, and moves them around.

Fig. 13.7

2)- Metaphase II, the sister chromatids are arranged at the metaphase plate.

3)- Anaphase II, the centromeres of sister chromatids separate and the separate sisters travel toward opposite poles.

44

4)- Telophase II, separated sister chromatids arrive at opposite poles.– Nuclei form around the chromatids.

• Cytokinesis separates the cytoplasm.• At the end of meiosis, there are four haploid

daughter cells.

Fig. 13.7

45

Crossing over

Recombinant Chromosomesمختلطة صبغيات

Chiasma

Fig. 13.10, Page 244

46

Crossing over Page 244

-Occurs during prophase I.

-The two homologous chromosomes joint together very closely.

-Two non-sister chromatids of the homologous chromosomes are crossed over at a chiasma point and exchange corresponding segments.

-The resulting chromosomes are called “recombinant chromosomes”.

-It is important in genetic variation in sexual life cycle.

47

• Three mechanisms contribute to genetic variation الوراثية :اإلختالفات1) independent assortment للكروموسومات الحر اإلنتقال2) crossing over العبور3) random fertilization العشوائى التلقيح

Sexual life cycles produce genetic variation among offspring

1)- Independent assortment: of chromosomes contributes to genetic variability due to the random orientation of tetrads at the metaphase plate.– There is a fifty-fifty chance

that a particular daughter cell of meiosis I will get the maternal chromosome of a

certain homologous pair and a fifty-fifty chance that it will receive the paternal chromosome.

Fig. 13.9

48

• Independent assortment alone would find each individual chromosome in a gamete that would be exclusively maternal or paternal in origin.

Fig. 13.10

3)- Crossing over: Homologous portions متماثلة of two أجزاء

non-sister chromatids exchange places, producing recombinant chromosomes which combine genes inherited from each parent.

2- The random fertilization: it adds to the genetic variation arising from meiosis.

• Any sperm can fuse with any egg.

49

• Mitosis produces two identical daughter cells, but meiosis produces 4 very different cells.

Fig. 13.8, Page 242

50

Comparison between Mitosis and meiosis • The chromosome number is reduced by half in meiosis, but not in mitosis.

– Mitosis produces daughter cells that are genetically identical to the parent and to each other.

– Meiosis produces cells that differ from the parent and each other.

• Three events, unique to meiosis, occur during the first division cycle.

1. During prophase I, homologous chromosomes pair up in a process called synapsis.– Later in prophase I, the joined homologous chromosomes are visible as a tetrad.– At X-shaped regions called chiasmata, sections of nonsister chromatids are

exchanged.– Chiasmata is the physical manifestation of crossing over, a form of genetic

rearrangement.

51

2. At metaphase I homologous pairs of chromosomes, not individual chromosomes are aligned along the metaphase plate.

• In humans, you would see 23 tetrads.

3. At anaphase I, it is homologous chromosomes, not sister chromatids, that separate and are carried to opposite poles of the cell.– Sister chromatids remain attached at the centromere until anaphase II.

• The processes during the second meiotic division are virtually identical to those of mitosis.

52Fig. 13.8, Page 242

Comparison between Mitosis and meiosis

• The behavior of chromosomes during meiosis and fertilization is responsible for most of the variation that arises each generation during sexual reproduction.

• Three mechanisms contribute to genetic variation:– independent assortment– crossing over– random fertilization

Sexual life cycles produce genetic variation among offspring

• Independent assortment of chromosomes contributes to genetic variability due to the random orientation of tetrads at the metaphase plate.– There is a fifty-fifty chance that a particular

daughter cell of meiosis I will get the maternal chromosome of a certain homologous pair and a fifty-fifty chance that it will receive the paternal chromosome.

Fig. 13.9

• Each homologous pair of chromosomes is positioned independently of the other pairs at metaphase I.

• Therefore, the first meiotic division results in independent assortment of maternal and paternal chromosomes into daughter cells.

• The number of combinations possible when chromosomes assort independently into gametes is 2n, where n is the haploid number of the organism.– If n = 3, there are eight possible combinations.– For humans with n = 23, there are 223 or about 8

million possible combinations of chromosomes.

• Independent assortment alone would find each individual chromosome in a gamete that would be exclusively maternal or paternal in origin.

• However, crossing over produces recombinant chromosomes which combine genes inherited from each parent.

Fig. 13.10

• Crossing over begins very early in prophase I as homologous chromosomes pair up gene by gene.

• In crossing over, homologous portions of two nonsister chromatids trade places.– For humans, this occurs two to three times per

chromosome pair.• One sister chromatid may undergo different

patterns of crossing over than its match.• Independent assortment of these nonidentical

sister chromatids during meiosis II increases still more the number of genetic types of gametes that can result from meiosis.

• The random nature of fertilization adds to the genetic variation arising from meiosis.

• Any sperm can fuse with any egg.– A zygote produced by mating of a woman and man

has a unique genetic identity.– An ovum is one of approximately 8 million possible

chromosome combinations (actually 223).– The successful sperm represents one of 8 million

different possibilities (actually 223).– The resulting zygote is composed of 1 in 70 trillion

(223 x 223) possible combinations of chromosomes.– Crossing over adds even more variation to this.

• The three sources of genetic variability in a sexually reproducing organism are:– Independent assortment of homologous

chromosomes during meiosis I and of nonidentical sister chromatids during meiosis II.

– Crossing over between homologous chromosomes during prophase I.

– Random fertilization of an ovum by a sperm.• All three mechanisms reshuffle the various

genes carried by individual members of a population.

• Mutations, still to be discussed, are what ultimately create a population’s diversity of genes.