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Dr. Aurelian Jovita Alexander
MDS
Dept. of Oral and Maxillofacial Pathology
Cells divide..
Reproduction
Growth
Repair
 Mitosis- is the process by which the genetic
material of eukaryotic cells is duplicated &
distributed during cell division
Mitosis (Gr. Mitos, thread; osis, condition)
 Meosis- The form of cell division by which
gametes, with half the number of chromosomes,
are produced
Meiosis (Gr. for deminition)
 is a membrane-enclosed organelle.
 Houses the genetic material, DNA, which is complexed with an array of
acidic & basic proteins into thin fibres
 During interphase, these fibres are uncoiled & dispersed into chromatin
 During mitosis & meiosis, chromatin fibres coil & condense into
structures called chomosomes
* Chromosomes,are the carriers of genetic material.
*They are made of DNA.
 Duplicated chromosome
 2 sister chromatids
 narrow at centromeres
 contain identical
copies of original DNA
Pair of chromosomes (maternal and paternal) that
 Are similar in shape and size, &
in the location of the centromere,
 Also contain same sequence
of gene sites or loci
 The state of being diploid, that is having two sets of
the chromosomes (and therefore two copies of genes)
 Human diploid cells have 46 chromosomes and human
haploid gametes (egg and sperm) have 23 chromosomes.
 located adjacent to the nucleus
 Found to contain 2 rod-shaped granules known as centrioles
 Associated with organization of microtubules
 small, cylindrical, microtubule-containing structures that are
embedded within the centrosome
 9 fibrillar units&
 Each fibrillar unit is found to contain 3 microtubles
 Involved in formation of spindle of microtubles
 Found in Animal cells & some plant cells
 Spindle fibres consist of microtubles, which themselves
consist of molecular subunits of the protein tubulin
 Seem to originate & grow out of centrioles
 Also originate from basal body, which is associated with
formation of cilia & flagella
 Kinetochore microtubles- which adhere to kinetochore
& responsible for chromosome migration during
anaphase
 Nonkinetochore microtubles or polar microtubules- which do
not adhere to kinetochores, makes contact with growing
microtubles from the opposite pole & maintain the separation
of the 2 poles during chromosome separation
Protein structure on
chromatids where the
spindle fibers attach
during cell division to pull
sister chromatids apart.
 It is the point at which the spindle microtubules make contact with the
chromosome.
 Each chromosome develops two kinetochores located on opposite sides
of the centromere, one associated with each of the two chromatids.
 Mitosis is the process by which a cell, which has previously
replicated each of its chromosomes, separates
the chromosomes in its cell nucleus into two identical sets of
chromosomes, each set in its own new nucleus
 It is a form of nuclear division
 Generally followed immediately by cytokinesis
 Mitosis and cytokinesis together define the mitotic
(M) phase of the cell cycle
 Takes place in somatic cells.
 Variations exist between different organisms.
 Higher Plant cells- Spindle has no centrioles
or asters at the poles
 Animal cells and lower plant cells- Complex
 Plant Meristems- Study
Total cell cycle: 12-24 hours
M phase:1 hour and Interphase: 23 hours.
 The phase of the cell cycle in which the cell spends the majority of its
time and performs the majority of its purposes including preparation
for cell division.
 Considered to be the 'living' phase of the cell.
Three stages :-
G1- Gap 1
S - Sythesis
G2- Gap 2
 The cell grows and functions normally.
 High amount of protein and mRNA synthesis
 The cell cycle lasts about 18 hours, and the
G1 phase takes up about 1/3 of that time.
 If the cell is not to divide again, it will
enter G0.
 The cell duplicates its DNA
(via semiconservative replication).
 Also known as the Swanson phase.
 Final subphase of Interphase in the cell
cycle directly preceding Mitosis.
 Rapid cell growth and protein synthesis
 G2 phase ends with the onset of prophase,
the first phase of mitosis in which the
cell’s chromatin condenses
into chromosomes.
 Cell cycle checkpoints are control mechanisms that
ensure the fidelity of cell division in eukaryotic cells.
 Important function -assess DNA damage, which is
detected by sensor mechanisms.
 When damage is found,
Signal mechanism
Effector mechanism.
STOP and GO chemical signals.
 Growth factor receptors in membranes which
are always tuned on
 family of proteins that control the progression of cells
through the cell cycle by activating cyclin-dependent
kinase (Cdk) enzymes
 activated by the formation of a complex with a cyclin and are
involved in the regulation of the cell cycle.
 The protein encoded by cdc2 gene functions as a protein
kinase & is dependent on another group of proteins known
as cyclins for activation
 Therefore it is called a cyclin-dependent kinase.
 Variety of different Cdk-cyclin complexes operate that
control eukaryotic cell cycles.
 To regulate Cdk activity in response to external signals,
regulation of cyclin gene expression, post-translational
modification ofCdks
* Phosphorylation-dephosphorylation cascades
*Interaction of cyclin/Cdk complexes with protein
inhibitors
 First checkpoint is located at the end of the cell
cycle's G1 phase
 Liver cells, for instance, enter mitosis only
around twice a year.
 Eukaryotes typically arrest the cell cycle if
environmental conditions make cell division
impossible.
 In animal cells, the G1 phase checkpoint is called
the restriction point, and in yeast cells it is called
the Start point.
 The restriction point is controlled mainly by action of the
CKI p16 (CDK inhibitor p16).
 This protein inhibits CDK4/6 – it can no longer interact with cyclin
D1 to cause cell cycle progression.
 In growth-induced or oncogenic-induced cyclin D expression,this
checkpoint is overcome - expression of cyclin D
 Once active CDK4/6-cyclin D complexes form, they phosphorylate
the tumor suppressor retinoblastoma protein (Rb).
 E2F is then able to cause expression of cyclin E
 CDK2
Controls the expression of
genes coding for products
needed for passage through
the G1 / S phase
Exerts its control by binding
to E2F transcription factor.
E2F transcription factor, in
the absence of bound Rb
protein, activates the
transcription of genes encoding
enzymes & other proteins
required for initiating DNA
replication.
 Activted by phosphorylation of the CDK by the
action of a "Maturation promoting factor"
 The molecular nature of this checkpoint involves an
activating phosphatase, - Cdc25- MPF- Cyclin B CDK
Complex.
 The cell cycle is arrested via inactivation of the
Cdc25 phosphatase.This is done by the ATM kinase
protein.
 The sensing mechanism ensures that the anaphase-
promoting complex(APC/C) is no longer inhibited-
free to degrade cyclin B, which harbors a D-box
(destruction box), and to break down securin
 A protein whose function is to inhibit separase,
which in turn cuts the cohesins
 Cohesins : proteins that hold sister
chromatids together prior to beginning of
anaphase.
 Securin : a protein that normally binds to and
inhibits an enzyme separase.
 Separase : a protein degrading enzyme.
 4 phases
 Prophase
 Metaphase
 Anaphase
 Telophase
 Appearance of chromosomes as thin threads inside the
nucleus.
 Condensation – folding
 Cells- Spheroid , Refractile ,Viscous
 Chromatids- Shorter and thicker
 Centrioles migrate along with the asters ,
circular path towards the poles,
 Until Antipodal positions.
 Prometaphase
 The nuclear envelope disintegrates and the
chromosomes are in apparent disorder.
 Fibres of the spindle that connect to chromosomes-
Chromosomal Fibres
 Those without interruption- Continuous Fibres
 Astral and Amphiastral- Animals and lower plants
 Anastral- Higher plants.
 The equilibrium of forces that characterises
metaphase- Broken
 Chromatids- migration towards pole.
 V Shape
 Equal arms- Metacentric
 Unequal arms- Submetacentric
 Microtubules of Chromosomal Fibres - 1/3rd to
1/5th
 Of the continuous fibres-
 Chromosomes-unfold
 Less Condensed
 Discontinuous segments of nuclear
envelope- ER
 Nucleoli reappear at the sites of the nucleolar
organisers.
 Cytokinesis
 Cytoplasm of a single eukaryotic cell is
divided to form two daughter cells.
• As compared with benign tumors & some well-differentiated
malignant neoplasms, undifferentiated tumors usually possess
large numbers of mitoses
• The presence of mitoses, however, does not necessarily indicate
that a tumor is malignant or that the tissue is neoplastic.
• Many normal tissues exhibiting rapid turnover, such as bone
marrow, have numerous mitoses, & non-neoplastic
proliferations such as hyperplasias contain many cells in
mitosis.
• More important as a morphologic feature of malignancy are
atypical, bizarre mitotic figures, sometimes producing tripolar,
quadripolar, or multipolar spindles
Proliferation markers
 proliferating cell nuclear antigen (PCNA)
 Ki67
 Minichromosome- maintenance protein2 (MCM2)
 cyclin D1
 Common & best known
 Its expression is seen in proliferating cells (G1, S, G2
phase), but not in resting cells (G0 phase)
 The mitotic abnormalities which occur
naturally in tumours can be divided into three
classes:
 Structural alterations in the chromosomes
 Numerical changes in the chromosome
complement
 Complete or partial suppression of the
spindle.
Mitosis

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Mitosis

  • 1. Dr. Aurelian Jovita Alexander MDS Dept. of Oral and Maxillofacial Pathology
  • 2.
  • 4.  Mitosis- is the process by which the genetic material of eukaryotic cells is duplicated & distributed during cell division Mitosis (Gr. Mitos, thread; osis, condition)  Meosis- The form of cell division by which gametes, with half the number of chromosomes, are produced Meiosis (Gr. for deminition)
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  • 6.  is a membrane-enclosed organelle.  Houses the genetic material, DNA, which is complexed with an array of acidic & basic proteins into thin fibres  During interphase, these fibres are uncoiled & dispersed into chromatin  During mitosis & meiosis, chromatin fibres coil & condense into structures called chomosomes
  • 7. * Chromosomes,are the carriers of genetic material. *They are made of DNA.
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  • 10.  Duplicated chromosome  2 sister chromatids  narrow at centromeres  contain identical copies of original DNA
  • 11. Pair of chromosomes (maternal and paternal) that  Are similar in shape and size, & in the location of the centromere,  Also contain same sequence of gene sites or loci
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  • 14.  The state of being diploid, that is having two sets of the chromosomes (and therefore two copies of genes)  Human diploid cells have 46 chromosomes and human haploid gametes (egg and sperm) have 23 chromosomes.
  • 15.  located adjacent to the nucleus  Found to contain 2 rod-shaped granules known as centrioles  Associated with organization of microtubules
  • 16.  small, cylindrical, microtubule-containing structures that are embedded within the centrosome  9 fibrillar units&  Each fibrillar unit is found to contain 3 microtubles  Involved in formation of spindle of microtubles  Found in Animal cells & some plant cells
  • 17.  Spindle fibres consist of microtubles, which themselves consist of molecular subunits of the protein tubulin  Seem to originate & grow out of centrioles  Also originate from basal body, which is associated with formation of cilia & flagella
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  • 19.  Kinetochore microtubles- which adhere to kinetochore & responsible for chromosome migration during anaphase
  • 20.  Nonkinetochore microtubles or polar microtubules- which do not adhere to kinetochores, makes contact with growing microtubles from the opposite pole & maintain the separation of the 2 poles during chromosome separation
  • 21. Protein structure on chromatids where the spindle fibers attach during cell division to pull sister chromatids apart.
  • 22.  It is the point at which the spindle microtubules make contact with the chromosome.  Each chromosome develops two kinetochores located on opposite sides of the centromere, one associated with each of the two chromatids.
  • 23.  Mitosis is the process by which a cell, which has previously replicated each of its chromosomes, separates the chromosomes in its cell nucleus into two identical sets of chromosomes, each set in its own new nucleus
  • 24.  It is a form of nuclear division  Generally followed immediately by cytokinesis  Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle  Takes place in somatic cells.
  • 25.  Variations exist between different organisms.  Higher Plant cells- Spindle has no centrioles or asters at the poles  Animal cells and lower plant cells- Complex  Plant Meristems- Study
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  • 28. Total cell cycle: 12-24 hours M phase:1 hour and Interphase: 23 hours.
  • 29.  The phase of the cell cycle in which the cell spends the majority of its time and performs the majority of its purposes including preparation for cell division.  Considered to be the 'living' phase of the cell. Three stages :- G1- Gap 1 S - Sythesis G2- Gap 2
  • 30.  The cell grows and functions normally.  High amount of protein and mRNA synthesis  The cell cycle lasts about 18 hours, and the G1 phase takes up about 1/3 of that time.  If the cell is not to divide again, it will enter G0.
  • 31.  The cell duplicates its DNA (via semiconservative replication).  Also known as the Swanson phase.
  • 32.  Final subphase of Interphase in the cell cycle directly preceding Mitosis.  Rapid cell growth and protein synthesis  G2 phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.
  • 33.  Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells.  Important function -assess DNA damage, which is detected by sensor mechanisms.  When damage is found, Signal mechanism Effector mechanism. STOP and GO chemical signals.
  • 34.  Growth factor receptors in membranes which are always tuned on
  • 35.  family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes
  • 36.  activated by the formation of a complex with a cyclin and are involved in the regulation of the cell cycle.  The protein encoded by cdc2 gene functions as a protein kinase & is dependent on another group of proteins known as cyclins for activation  Therefore it is called a cyclin-dependent kinase.  Variety of different Cdk-cyclin complexes operate that control eukaryotic cell cycles.
  • 37.  To regulate Cdk activity in response to external signals, regulation of cyclin gene expression, post-translational modification ofCdks * Phosphorylation-dephosphorylation cascades *Interaction of cyclin/Cdk complexes with protein inhibitors
  • 38.  First checkpoint is located at the end of the cell cycle's G1 phase  Liver cells, for instance, enter mitosis only around twice a year.  Eukaryotes typically arrest the cell cycle if environmental conditions make cell division impossible.  In animal cells, the G1 phase checkpoint is called the restriction point, and in yeast cells it is called the Start point.
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  • 40.  The restriction point is controlled mainly by action of the CKI p16 (CDK inhibitor p16).  This protein inhibits CDK4/6 – it can no longer interact with cyclin D1 to cause cell cycle progression.  In growth-induced or oncogenic-induced cyclin D expression,this checkpoint is overcome - expression of cyclin D  Once active CDK4/6-cyclin D complexes form, they phosphorylate the tumor suppressor retinoblastoma protein (Rb).  E2F is then able to cause expression of cyclin E  CDK2
  • 41. Controls the expression of genes coding for products needed for passage through the G1 / S phase Exerts its control by binding to E2F transcription factor. E2F transcription factor, in the absence of bound Rb protein, activates the transcription of genes encoding enzymes & other proteins required for initiating DNA replication.
  • 42.  Activted by phosphorylation of the CDK by the action of a "Maturation promoting factor"  The molecular nature of this checkpoint involves an activating phosphatase, - Cdc25- MPF- Cyclin B CDK Complex.  The cell cycle is arrested via inactivation of the Cdc25 phosphatase.This is done by the ATM kinase protein.
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  • 44.  The sensing mechanism ensures that the anaphase- promoting complex(APC/C) is no longer inhibited- free to degrade cyclin B, which harbors a D-box (destruction box), and to break down securin  A protein whose function is to inhibit separase, which in turn cuts the cohesins
  • 45.  Cohesins : proteins that hold sister chromatids together prior to beginning of anaphase.  Securin : a protein that normally binds to and inhibits an enzyme separase.  Separase : a protein degrading enzyme.
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  • 47.  4 phases  Prophase  Metaphase  Anaphase  Telophase
  • 48.  Appearance of chromosomes as thin threads inside the nucleus.  Condensation – folding  Cells- Spheroid , Refractile ,Viscous
  • 49.  Chromatids- Shorter and thicker
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  • 51.  Centrioles migrate along with the asters , circular path towards the poles,  Until Antipodal positions.
  • 52.  Prometaphase  The nuclear envelope disintegrates and the chromosomes are in apparent disorder.  Fibres of the spindle that connect to chromosomes- Chromosomal Fibres  Those without interruption- Continuous Fibres  Astral and Amphiastral- Animals and lower plants  Anastral- Higher plants.
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  • 54.  The equilibrium of forces that characterises metaphase- Broken  Chromatids- migration towards pole.  V Shape  Equal arms- Metacentric  Unequal arms- Submetacentric  Microtubules of Chromosomal Fibres - 1/3rd to 1/5th  Of the continuous fibres-
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  • 56.  Chromosomes-unfold  Less Condensed  Discontinuous segments of nuclear envelope- ER  Nucleoli reappear at the sites of the nucleolar organisers.  Cytokinesis
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  • 58.  Cytoplasm of a single eukaryotic cell is divided to form two daughter cells.
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  • 63. • As compared with benign tumors & some well-differentiated malignant neoplasms, undifferentiated tumors usually possess large numbers of mitoses • The presence of mitoses, however, does not necessarily indicate that a tumor is malignant or that the tissue is neoplastic. • Many normal tissues exhibiting rapid turnover, such as bone marrow, have numerous mitoses, & non-neoplastic proliferations such as hyperplasias contain many cells in mitosis. • More important as a morphologic feature of malignancy are atypical, bizarre mitotic figures, sometimes producing tripolar, quadripolar, or multipolar spindles
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  • 66. Proliferation markers  proliferating cell nuclear antigen (PCNA)  Ki67  Minichromosome- maintenance protein2 (MCM2)  cyclin D1
  • 67.  Common & best known  Its expression is seen in proliferating cells (G1, S, G2 phase), but not in resting cells (G0 phase)
  • 68.  The mitotic abnormalities which occur naturally in tumours can be divided into three classes:  Structural alterations in the chromosomes  Numerical changes in the chromosome complement  Complete or partial suppression of the spindle.