DR.TASNIM ARA JHILKY

MD part II

Phase_ A

Biochemistry department

Sir Solimullah Medical College,Midford Dhaka

CELL CYCLE

.

Cell cycleM

Mitosis

G1

Gap 1

G0

Resting

G2

Gap 2

S

Synthesis

Cell has a “life cycle”

cell is formed from

a mitotic division

cell grows & matures

to divide again

cell grows & matures

to never divide again

G1, S, G2, M G1G0

epithelial cells,

blood cells,

stem cells

liver cells

brain / nerve cells

muscle cells

Cell cycle phases G1 phase-growth and synthesis (hrs to yrs)

S phase- DNA synthesis phase(7 hrs)

G2 phase-Preparation for division(upto 5 hrs)

M phase-M phase includes the overlapping processes of mitosis and cytokinesis(1 to 2 hrs)

Combination of G1,S,G2 phage is known as interphage

90% of cell life cycle

cell doing its “everyday job”

produce RNA, synthesize proteins/enzymes

prepares for duplication if triggered

Phases of cell cycle……

Representation of mitosis stages

Check Point

.

Checkpoint

G1-S checkpoint…..

G2 checkpoint….

M checkpoint….

Importance of checkpoint

Regulation of cell cycle Cell cycle regulation is necessary for healthy growth

Regulation of cell cycleInternal and external factors regulate cell division.

External factors include physical and chemical signals.

Growth factors are proteins that stimulate cell division.

Two of the most important internal factors are kinases and cyclins. Cyclin: group of proteins that triggers action of kinases.it is so

named because of the cyclic nature of their production and degradation.more than 15 cyclin identified.cyclin D,E,A,B appear sequentially during cell cycle.

Kinase: enzymes that affect molecule’s activity Together these both help a cell advance to different stages of

the cell cycle.the cyclin cdk complex phosphorylates crucial target proteins that drive the cell through cell cycle .on completion cyclin levels decline rapidly.

• External factors trigger internal factors,

which affect the cell cycle.

External growth factors

Cyclins

Kinases

Triggered cell cycle

activities

Regulation of cell cycle:The orderly

progression of cells through the

various phases of cell cycle is

arranged by

cyclins and cyclin-dependent kinases

(CDKs), and

by their inhibitors.

Fundamental principles of carcinogenesis:

Nonlethal genetic damage lies at the heart of carcinogenesis-Such

genetic damage (or mutation) may be acquired by the action of

environmental agents, such as chemicals, radiation, or viruses, or it

may be inherited in the germ line.

tumors are monoclonal: A tumor is formed by the clonal expansion of

a single precursor cell that has acquired genetic damage.

Principal Targets of Genetic Damage:

4 Classes of Normal Regulatory Genes

Growth-promoting proto-oncogenes

Growth-inhibiting tumor suppressor genes

Apoptosis-regulating genes; genes that regulate the programmed cell death

DNA repair genes

Carcinogenesis is a multistep process resulting from the accumulation of

multiple mutations at phenotypic and genotypic levels.

these mutations accumulate independently in different clonal cells,

generating subclones with varying abilities to grow, invade, metastasize,

and resist (or respond to) therapy.

Over a period of time tumors not only increase in size but become more

aggressive and acquire greater malignant potential (tumor progression)

Essential alterations for malignant

transformation

1. Self-sufficiency in growth signals: Tumors have the capacity to

proliferate without external stimuli, usually as a consequence of

oncogene activation.

2. Insensitivity to growth-inhibitory signals : Tumors may not respond

to molecules that are inhibitory to the proliferation of normal cells

such as transforming growth factor β (TGF-β) and direct inhibitors of

cyclin-dependent kinases (CDKIs).

Cont………… .3. Evasion of apoptosis: Tumors may be resistant to programmed cell

death, as a consequence of inactivation of p53 or activation of anti-

apoptotic genes.

4. Limitless replicative potential: Tumor cells have unrestricted

proliferative capacity, avoiding cellular senescence and mitotic

catastrophe.

•5. Sustained angiogenesis: Tumor cells, like normal cells, are not able

to grow without formation of a vascular supply to bring nutrients and

oxygen and remove waste products. Hence, tumors must induce

angiogenesis.

•6. Ability to invade and metastasize : Tumor metastases are the cause of

the vast majority of cancer deaths and depend on processes that are

intrinsic to the cell or are initiated by signals from the tissue

environment.

Con………..

.•7. Defects in DNA repair : Tumors may fail to repair DNA damage

caused by carcinogens or incurred during unregulated cellular

proliferation, leading to genomic instability and mutations in proto-

oncogenes and tumor suppressor genes.

Another important change for tumor development is escape from

immune attack .

Self-sufficiency in growth signals

(Oncogenes)

Genes that promote autonomous cell growth in cancer cells ,are called

oncogenes.

Their unmutated cellular counterpart are called proto-oncogene.

Oncogenes are created by mutations in proto-oncogene and are

characterized by the ability to promote cell growth in the absence of

normal groth promoting signals .

Their products called onco proteins ,resemble the normal product of

proto-oncogenes except that onco protein are devoid of any signal for

growth.

In this way they become autonomus.

Normal cell ProliferationThe binding of a growth factor to its specific receptor

Transient and limited activation of the growth factor receptor

Activates several signal-transducing proteins on the inner leaflet of the plasma membrane

Transmission of the transduced signal across the cytosol to the nucleus via second messengers or by a cascade of signal transduction molecules

Induction and activation of nuclear regulatory factors that initiate DNA transcription

Entry and progression of the cell into the cell cycle, ultimately resulting in cell division

Proto-oncogene,oncogene .

In a normal cell, Proto-oncogenes have multiple roles, participating in

cellular functions related to growth and proliferation.

Self sufficiency for growth to a cancerous cell is provided by oncogenes,

which are the mutant proto-oncogenes.

Mutations convert inducible proto-oncogenes into constitutively active

oncogenes, which is responsible for progressive cell divisions.

Oncogenes

Growth factorsGrowth factor

receptors

Signal transduction

proteins

Nuclear regulatory proteins

Cell cycle regulators

Growth Factors

Normally cell require stimulation by GFs to undergo

proliferation.

Mostly these GFs are secreted by one cell type and act on a

neighboring cell to stimulate proliferation. (paracrine action)

Cancer cells acquire the ability to synthesize their own GFs

generating an autocrine loop.

Examples: - Glioblastomas secrete PDGF

- Sarcomas secrete TGF-α

Growth Factor Receptors

Several oncogenes that encode growth factor receptors have been

found.

Ex. Transmembrane proteins with an external ligand-binding domain and

a cytoplasmic tyrosine kinase domain.

In the normal forms of these receptors, the kinase is transiently

activated.

The oncogenic versions of these receptors, kinase is constitutively

activated. Resulting in continuous mitogenic signals to the cell, even

in the absence of growth factor in the environment

Signal-Transducing Proteins signal-transducing proteins plays an important role in signaling

cascades downstream of growth factor receptors, resulting in

mitogenesis.

RAS is a signal transducing oncoprotein belonging to family of GTP-

binding proteins (G proteins). Point mutation of RAS family genes

(HRAS, KRAS, NRAS) is the single most common abnormality of

proto-oncogenes in human tumors.

KRAS- colon and pancreas

HRAS- bladder tumors

NRAS- hematopoietic tumors.

Approximately 15% to 20% of all human tumors contain mutated

versions of RAS proteins.

Alteration in nonrecptor kinases

In CML and some acute lymphoblastic leukemias, the ABL

gene is translocated from its normal habitat on chromosome

9 to chromosome 22. The resultant chimeric gene encodes a

constitutively active, oncogenic BCR-ABL tyrosine kinase.

Nuclear Regulatory Proteins(Transcription Factors)

all signal transduction pathways converge to the nucleus where

stimulation of nuclear transcription factors allow them for DNA

binding. Binding of these proteins to specific sequences in the genomic

DNA activates transcription of genes.

Growth autonomy may thus occur as a consequence of mutations

affecting genes that regulate transcription.

Cell Cycle Regulators(Cyclins and Cyclin-Dependent Kinases)

The ultimate outcome of all growth-promoting stimuli is the entry of

quiescent cells into the cell cycle. Cancers may grow autonomously if the

genes that drive the cell cycle become dysregulated by mutations or

amplification.

Example of cell cycle regulator genes and associated cancers:

• Overexpression of cyclin D genes - cancer of breast, esophagus, liver,

and a subset of lymphomas.

• Amplification of the CDK4 gene - melanomas, sarcomas, and

glioblastomas.

While cyclins arouse the CDKs, their inhibitors (CDKIs) silence the

CDKs and exert negative control over the cell cycle. The CDKIs are

frequently mutated or otherwise silenced in many human malignancies.

• Germline mutations of p16 - melanoma.

• Somatically acquired deletion or inactivation of p16 - pancreatic

carcinomas, glioblastomas, esophageal cancers, acute lymphoblastic

leukemias, non-small-cell lung carcinomas, soft-tissue sarcomas, and

bladder cancers.

. RB protein, the product of the RB gene, is a ubiquitously

expressed nuclear phosphoprotein that plays a key role in

regulating the cell cycle.

germline loss or mutations of the RB gene -

retinoblastomas and osteosarcomas.

Somatically acquired RB mutations - glioblastomas,

small-cell carcinomas of lung, breast cancers, and bladder

carcinomas.

Insensitivity to Growth-Inhibitory Signals

(Tumor Suppressor Gene)

Failure of growth inhibition is one of the fundamental alterations in

the process of carcinogenesis. Whereas oncogenes drive the

proliferation of cells, the products of tumor suppressor genes apply

brakes to cell proliferation.

It has become apparent that the tumor suppressor proteins form a

network of checkpoint that prevent uncontrolled growth..

There are so many tumor suppressor includesTGF-B,NF1,NF2,RB1

P53 ,BRCA1,BRCA2.

• The p53 gene is located on chromosome 17p13.1, and it is the most

common target for genetic alteration in human tumors.

• p53 acts as a “molecular policeman” that prevents the propagation of

genetically damaged cells.

• P53 inhibits neoplastic transformation by three interlocking

mechanisms: activation of temporary cell cycle arrest (quiescence),

induction of permanent cell cycle arrest (senescence), or triggering of

programmed cell death (apoptosis).

• Homozygous loss of p53 occurs in virtually every type of cancer,

including carcinomas of the lung, colon, and breast—the three leading

causes of cancer death.

Role of p53 in Maintaining the Integrity of Genome

Limitless Replicative Potential

most normal human cells have a capacity of 60 to 70 doublings. After

this, the cells lose their ability to divide and become senescent. This

phenomenon has been ascribed to progressive shortening of telomeres

at the ends of chromosomes.

Defects in DNA repair Although humans literally swim in environmental agents that are

mutagenic (e.g., chemicals, radiation, sunlight), cancers are relatively

rare outcomes of these encounters. This state of affairs results from the

ability of normal cells to repair DNA damage and the death of cells

with unrepairable damage.

Defects in three types of DNA-repair systems contribute to different

types of cancers

mismatch repair,

nucleotide excision repair, and

recombination repair

Chemical Carcinogenesis

Viral CarcinogenesisHuman papilloma virus (HPV)

Epstein-Barr virus (EBV)

Hepatitis B virus (HBV)

Human T-cell leukemia virus type 1(HTLV-1)

These viruses have the potential to induce the carcinogenesis,by causing the mutation of various genes regulating normalcellular function

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