Bài giảng tế bào học động vật phần 2

Meiosis II • Daughter cells undergo a second division; much like mitosis • NO ADDITIONAL REPLICATION OCCURS Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 17... Kinase là enzyme xúc tác quá trìn

CHU KỲ TẾ BÀO

(Cell cycle)

Khái niệm về chu kỳ tế bào

đặc tính cơ bản của cơ thể sống; tự sinh ra cơ thể giống mình

1885: Virchow  động vật sinh ra động vật; thực vật sinh ra thực vật; tế bào chỉ được sinh ra từ tế bào có trước

1882: Flemming  hiện tượng phân bào có tơ (mitosis)

Phân bào có xen kẻ bởi thời gian sinh trưởng

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 3

Các kỳ của chu kỳ tế bào

Gian kỳ (interphase)

• Trao đổi chất, sinh trưởng, chuẩn bị cho phân bào

• G1 S  G2

Kỳ phân bào (mitosis)

• Tế bào mẹ phân chia thành 2

tế bào con

• M (Prometaanatelophase)

Gian kỳ

(Interphase)

Pha G1 (Gap I phase)

• Ngay sau khi tế bào được phân chia cho

đến khi bắt đầu pha S

• Thời gian tùy thuộc chức năng tế bào:

TB phôi (30’-1g); TB gan (1 năm); TN

neuron: suốt đời

• Cuối G1: điểm chốt R; Vấn đề G0

Tổng hợp ở pha G1

• Tổng hợp RNA và protein  pha sinh trưởng

• TB phôi có G1 ngắn  các nhân tố cần cho S phase được chuẩn bị trước và dự trữ trong TB chất;

• Phát triển phôi: do G1 ngắn, các gene hoạt hóa khác nhau  tổng hợp protein đặc thù  tạo các dòng tế bào biệt hóa  GC

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 5

Pha S (S phase)

• Tiếp theo pha G1, khi vượt qua R (thông qua tổng hợp cyclin A)

• Cyclin A+kinase  tái bản DNA  nhân đôi NST

• Thời gian pha S: 6-8 giờ

Pha G2 (Gap 2 phase)

• Tiếp theo pha S  pha G2

• Thời gian pha S: 4-5 giờ

• Tổng hợp RNA và protein  sinh trưởng TB

• Tái cấu trúc bào quan  chuẩn bị phân chia TB

• Cuối G2: tổng hợp cyclin B;

Pha phân bào (mitosis)

• Tiếp theo pha G2, tế bào mẹ phân chia thành 2 tế bào con

• Truyền thông tin di truyền từ mẹ sang con

• Phân chia tế bào chất  quá trình tổng hợp cho G1

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 7

MITOSIS

Mitosis begins after G 2 and ends before G 1

Prophase

• Chromosome condense

• Microtubles form

• The nuclear envelope breaks down

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 9

Anaphase

• Centromeres divide

• Spindle fibers pull one set of chromosomes to each pole

• Precise alignment is critical to division

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 11

– animals - pinching of plasma membrane

– plants- elongates and the cell plate forms

(future cell wall and cell membrane)

Meiosis I: Metaphase I

• Tetrads or homologous

chromosomes move to

center of cell

Meiosis I: Telophase I

• Daughter nuclei formed

• These are haploid (1n)

Meiosis II

• Daughter cells undergo a second division; much like

mitosis

• NO ADDITIONAL REPLICATION OCCURS

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 17

Meiosis II: Prophase II

• Spindle fibers form again

Meiosis II: Metaphase II

Sister chromatids move to the center Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 19

Meiosis II: Anaphase II

• Centromeres split

• Individual chromosomes

are pulled to poles

Meiosis II: Telophase II & Cytokinesis

• Four haploid daughter

cells results from one

original diploid cell

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Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 23

Cell cycle check points

Kinase là enzyme xúc tác quá trình chuyển nhóm phospho từ gốc

cao năng lượng đến cơ chất đặc biệt

Cyclin- Cdk

Cyclin: là protein, xuất hiện theo chu kỳ (cycle  cyclin)

Cdk (cyclin dependent kinase): phát động quá trình phosphoryl hóa các serin và thereonin

Cyclin kết hợp Cdk  Cdk có hoạt tính và ngược lại

Tế bào phôi sớm (early embryo development)

MPF (maturation promoting factor)

 Vượt qua G2 vào M phase

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Regulation of Cell Division

Coordination of cell division

A multicellular organism needs to coordinate cell

division across different tissues & organs

– critical for normal growth,

development & maintenance

• coordinate timing of cell division

• coordinate rates of cell division

• not all cells can have the same cell cycle

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G 2

M metaphase prophase

anaphase telophase

interphase (G 1 , S, G 2 phases) mitosis (M)

• retain ability to divide, but keep it in reserve

• divide once every year or two

– mature nerve cells & muscle cells

• do not divide at all after maturity

• permanently in G0

Frequency of cell division

Overview of Cell Cycle Control

• Two irreversible points in cell cycle

– replication of genetic material – separation of sister chromatids

Checkpoint control system

Checkpoints

– cell cycle controlled by STOP & GO chemical signals at

critical points

– signals indicate if key cellular

processes have been

completed correctly

Checkpoint control system

• are all chromosomes attached to spindle?

• can sister chromatids separate correctly?

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G1/S checkpoint

G1/S checkpoint is most critical

– primary decision point

• “ restriction point ”

– if cell receives “GO” signal, it divides

• internal signals: cell growth (size), cell nutrition

• external signals: “growth factors”

– if cell does not receive

signal, it exits cycle &

switches to G0 phase

• non-dividing, working state

G0 phase

M Mitosis

G1 Gap 1

G0 Resting

– non-dividing, differentiated state

• liver cells

 in G0, but can be “called

back” to cell cycle by external cues

• nerve & muscle cells

How do cells know when to divide?

• chemical signals in cytoplasm give cue

• signals usually mean proteins

– activators – inhibitors

Activation of cell division

• either activates or inactivates cell signals

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 35

Cell cycle signals

• Cell cycle controls

• phosphorylates cellular proteins

– activates or inactivates proteins

Cyclins & Cdks

Interaction of Cdk’s & different cyclins triggers the stages

of the cell cycle

Cdk / G1 cyclin

Cdk / G2 cyclin (MPF)

Spindle checkpoint

• Growth factors

Cyclin & Cyclin-dependent kinases

CDKs & cyclin drive cell from one phase to next in cell

cycle

cycle is so key to life that

the genes for these

regulatory proteins have

been highly conserved

through evolution

same in yeast, insects,

plants & animals (including

humans)

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 39

External signals

• Growth factors

– coordination between cells

– protein signals released by body cells

that stimulate other cells to divide

• density-dependent inhibition

– crowded cells stop dividing – each cell binds a bit of growth factor

» not enough activator left to trigger division

in any one cell

Growth factor signals

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 41

Example of a Growth Factor

Platelet Derived Growth Factor (PDGF)

– made by platelets in blood clots

– binding of PDGF to cell receptors stimulates cell division in connective tissue

• heal wounds

Growth Factors and Cancer

Growth factors can create cancers

– proto-oncogenes

• normally activates cell division

– growth factor genes – become oncogenes (cancer-causing) when mutated

• if switched “ON” can cause cancer

• example: RAS (activates cyclins)

– tumor-suppressor genes

• normally inhibits cell division

• if switched “OFF” can cause cancer

• example: p53

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 43

Cancer & Cell Growth

• Cancer is essentially a failure

of cell division control

– unrestrained, uncontrolled cell growth

• What control is lost?

– gene p53 plays a key role in G1/S restriction point

• p53 protein halts cell division if it detects damaged DNA

– options:

» stimulates repair enzymes to fix DNA

» forces cell into G0 resting stage

» keeps cell in G1 arrest

» causes apoptosis of damaged cell

• ALL cancers have to shut down p53 activity

p53 is the

Cell Cycle

Enforcer

DNA damage is caused

by heat, radiation, or

chemicals

p53 allows cells with repaired DNA to divide

Damaged cells continue to divide

If other damage accumulates, the cell can turn cancerous

Step 3 p53 triggers the destruction

of cells damaged beyond repair

ABNORMAL p53

NORMAL p53

abnormal p53 protein

cancer cell

Step 2

DNA repair enzyme

p53 protein

p53 protein

p53 — master regulator gene

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Bài 7: The Biology of Cancer

“Death in old age is inevitable, but death before old age is not.”

Basic concepts of Cancer cell biology

Tại Việt Nam, thống kê cho thấy các ca mắc ung thư ngày càng có

xu hướng tăng lên Từ con số 68.000 ca mắc ung thư năm 2000

đã tăng lên 126.000 năm 2010 và dự kiến sẽ vượt qua 190.000

ca vào 2020 (Nguồn: Dân trí, 6/10/2020)

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 47

PGS.TS Mai Xuân Khẩn, Bệnh viện Quân y 103; 16/04/2020

Số ca mắc mới ung thư trên toàn cầu

trong năm 2020 Nguồn: Globocan

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Số ca mắc mới ung thư trên toàn

cầu trong năm 2020

Nguồn: Globocan

Cancer Rates

Females Males

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Source: Globocan 2020

Số ca mắc mới ung thư ở VN trong

năm 2020 Nguồn: GlobocanNguyen Ngoc Tan, PhD; BIO-NLU, 2022 53

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 55

What is cancer?

Cancer is the abnormal proliferation of any of the different kind of cell

Cancer- Latin word which means “Crab”

• Cancer is defined as the continuous uncontrolled growth of cells

• A tumor is a any abnormal proliferation of cells

• Benign tumors stays confined to its original location

• Malignant tumors are capable of invading surrounding tissue or invading the entire body

• Tumors are classified as to their cell type

• Tumors can arise from any cell type in the body Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 57

The simplest definition is from

According to the ACS, cancer is a group of diseases

characterized by uncontrolled growth and spread of

If the spread is not controlled, it can result in death

The hallmark of cancer

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• turn off suicide genes

– immortality = unlimited divisions

• turn on chromosome maintenance genes

– promotes blood vessel growth

• turn on blood vessel growth genes

– overcome anchor & density dependence

• turn off touch-sensor gene

It’s like an out-of-control car with many systems failing!

What causes these “hits”?

Mutations in cells can be triggered by

Tumors

Mass of abnormal cells

– Benign tumor

• abnormal cells remain at original site as a lump

– p53 has halted cell divisions

• most do not cause serious problems & can be removed by surgery

– Malignant tumor

• cells leave original site

– lose attachment to nearby cells – carried by blood & lymph system to other tissues – start more tumors = metastasis

• impair functions of organs throughout body

Do not

metastasize

Can spread distantly (metastasis)

Mitotic index = rate of growth

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Large # of dividing cells

Large, variably shaped nuclei

Large nucleus to cytoplasm ratio

Variation in size and shape

Loss of normal cell features

Disorganized arrangement

Characteristics of Cancer Cells

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Types of Cancers

On the basis of cell type On the basis of tissue of origin

• Carcinoma

epithelial cell 90% of all tumours derived from ectoderm (mostly) or endoderm (some)

• Sarcoma

connective tissue 2% of all tumours derived from mesoderm

• Leukaemia

circulatory or lymphatic 8% of all tumours

derived from mesoderm

Classification and nomenclature

We can group cancer according to the type of cell they start

in There are 5 main types These are:

carcinoma – this cancer begins in the skin or in tissues that line or cover internal organs There are different subtypes, including adenocarcinoma, basal cell carcinoma, squamous cell carcinoma and transitional cell carcinoma

sarcoma – this cancer begins in the connective or supportive tissues such as bone, cartilage, fat, muscle or blood vessels

leukaemia – this is cancer of the white blood cells It starts in the tissues that make blood cells such as the bone marrow

lymphoma and myeloma – these cancers begin in the cells of the immune system brain and spinal cord cancers – these are known as central nervous system cancers

We can also classify cancers according to where they start

in the body, such as breast cancer, liver or lung cancer

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Childhood cancers differ from adult cancers

Classification by tissue type:

(stem cells, progenitor cells, de-differentiation, increased risk with age)

MOST CHILDHOOD CANCERS

(failures of differentiation, other losses of replication control, decreased risk with age except for osteosarcoma)

Adult Cancer Risk Increases

with Age (~40% get it, in lifetime)

due to

(1) sequential accumulation of mutations over a

long time

(2) senescence-related tissue changes that can

promote cancer development

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 69

Crespi 2011, PRSLB

Pediatric Cancer Risk decreases with age & parallels growth velocity; 2nd

leading cause of child death in developed countries

271.520 300.430

Percent Name Name Percent

26 Lung & bronchus Lung & bronchus 28

2 Liver and intrahepatic bile

duct

2 Brain/other nerveous

system

Kidney and renal pelvic 3

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Three phase in development of Cancer cells

Initiation: a single cell undergoes a

mutation that cause it to divide

repeatedly

Promotion: a tumor develops and

cells within the tumor mutate

Progression: a cell mutates in such

a way that allow it to invade

surrounding tissue

 metastasis

Metastasis

Carcinoma: derived from endoderm or ectoderm

Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 73

Events in metastasis

Viruses and Cancer

Implicated

– Epstein-Barr virus (EBV)

– Kaposi’s sarcoma herpes virus (KSHV)

– Human papillomavirus (HPV)

– Human T cell leukemia–lymphoma virus (HTLV)

Nobel prize 2020: Physiology or Medicine

Drs Harvey J Alter, Michael Houghton and Charles M

the hepatitis C virus The Nobel committee said the

three scientists had “made possible blood tests and new medicines that have saved millions of lives.” Nguyen Ngoc Tan, PhD; BIO-NLU, 2022 77

More information…

Bacterial Cause of Cancer

Helicobacter pylori

– Chronic infections are associated with:

• Peptic ulcer disease

• Stomach carcinoma

• Mucosa-associated lymphoid tissue lymphomas

Inflammation and Cancer

Chronic inflammation is an important factor in development of cancer

• Cytokine release from inflammatory cells

• Free radicals

• Mutation promotion

• Decreased response to DNA damage

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Environmental Risk Factors

Tobacco

• Multipotent carcinogenic mixture

• Linked to cancers of the lung, lower urinary tract, aerodigestive tract, liver, kidney, pancreas, cervix

• Linked to myeloid leukemia

• Poor gene repair

• Changes in gap junction intercellular communication

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Ultraviolet radiation

• Causes basal cell carcinoma, squamous cell carcinoma, and melanoma

• Principal source is sunlight

• Ultraviolet A (UVA) and ultraviolet B (UVB)

• Promotes skin inflammation and release of free radicals

Alcohol consumption

• Risk factor for oral cavity, pharynx, hypopharynx, larynx, esophagus, and liver cancers

• Cigarette/alcohol combination increases a person’s risk

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