CELL CYCLE

SPEAKER-Dr.Ayesha.Juhi Coordinator-Dr.Ravindra.P.N

Introduction
In 1858 the pathologist Rudolph Virchow coined the cell doctrine which states that "When a cell arises, there must have been a previous cell, just as animals can only arise from animals and plants from plants."

Cells are generated from cells and the only way to make more cells is by division of those that already exists. Repeated cycles of cell growth and division result in development of a single fertilized egg into the more than 103 cells that make up the human body.

Introduction
Definition: It is process by which cell reproduces by performing an orderly sequence events in which it duplicates its contents and then divides into two.

Ref: The molecular biology of cell

AN OVERIEW OF THE CELL CYCLE

State

Phase

Abbreviation

Description
A resting phase where the cell has left the cycle and has stopped dividing.
Cells increase in size in Gap 1..

Quiescent/ senescent

Gap 0 Gap 1

G0 G1 S G2

Interphase

Synthesis Gap 2

DNA replication occurs during this phase.

During the gap between DNA synthesis and mitosis, the cell will continue to grow. Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells..

Cell division

Mitosis

Gap 1-phase
The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis. It is also called the growth phase. During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species.

S-phase
S phase starts
when DNA synthesis commences; When it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled. It is the longest phase of the cell cycle.

G2 -phase
G2 phase, which lasts until the cell enters mitosis. Again, significant biosynthesis occurs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis.

Mitosis

Stages of Mitosis
1.Prophase The chromosomes gradually condense and appear as strands that become thicker and shorter; - The nuclear envelope breaks up. 2.Metaphase The chromosomes are condensed; - A mitotic spindle is formed of microtubules; - Microtubules attach to the centromeres on chromosomes and to the centrioles at opposite poles of the cell 3.Anaphase The chromatids separate and move to opposite poles 4.Telophase The chromatids are at opposite poles of the cells - The nuclear envelope is formed 5.Cytokinesis Division of the cytoplasm mediated by actin filamen

Regulation of cell cycle

A major cell cycle regulatory point occurs in late G1 phase and controls progression from G1 to S. This regulatory point was first defined by studies of budding yeast (Saccharomyces cerevisiae),where it is called as START Once cells have passed START, they are committed to enter S phase. In addition to serving as a decision point for monitoring extracellular signals,START is the point at which cell growth is coordinated with DNA REPLICATION and CELL DIVISION.

In humans
The proliferation of cells is similarly regulated in G1 phase by a decision point analogous to START called as RESTRICTION POINT. In the presence of appropriate growth factors cell pass this point and enter S phase. In the absence of growth factors the cells enter into G0 phase.

Cell Cycle Checkpoints

In most cells there are several points in the cell cycle called CHECKPOINTS.

REGULATORS OF CELL CYCLE PROGRESSION

One of the most exciting developments of last few decades has been the elucidation of molecular mechanism that control the progression of eukaryotic cells through the division of cell. Scientist 1971 Yoshio Mauci and Clement Dennis Smith and Robert Ecker 1970 Lee Hartwell Paul Nurse 1983 Tim Hunt Discovery MPF MATURATION PROMOTING FACTOR cdc28(cell division cycle) cdc2 Cyclins (A ,B)

Families of cyclins and cyclin dependent kinases

The cell cycles of higher eukaryotes are controlled not only by multiple cyclins but also by multiple cdc2 related protein kinases-cdks CYCLIN DEPENDENT KINASES.

MPF(Dimer of cdc2 and Cyclin B)

REGULATION OF Cdks

Role of MPF and its degradation

Cdk inhibitors(CKI)

Active complexes of cyclins and CDKs exert their biological effects by phosphorylating proteins During the G1 phase, a major target of cyclin/CDK complexes is the retinoblastoma protein (pRb).

pRb is a growth-suppressing protein whose activity is controlled by whether or not it is phosphorylated

pRb
When pRb is in the dephosphorylated form, during the G0 phase and early in the G1 phase, it is active . pRb exerts its growth-suppressing effects by binding to many cellular proteins, including the transcription factors of the E2F family E2F transcription factors regulate the expression of numerous genes that are expressed during G1, or at the transition from the G1 to the S phase, to initiate DNA replication. pRb that is bound to an E2F transcription factor inhibits the transcription factor's activity. Following phosphorylation by cyclin/CDK complexes, pRb dissociates from E2F, allowing the transcription factor to bind DNA sequences and activate the expression of genes necessary for the cell to enter the S phase.

MASTER WATCHMAN GENE (guardian angel gene) p53

p53

The p53 protein senses DNA damage and can halt progression of the cell cycle in G1 (by blocking the activity of Cdk2 Under normal circumstances p53 levels remain very low due to its interaction with a member of the ubiquitin ligase family called MDM2. The p53 protein is also a key player in apoptosis, forcing "bad" cells to commit suicide. So if the cell has only mutant versions of the protein, it can live on perhaps developing into a cancer. More than half of all human cancers do, in fact, harbor p53 mutations and have no functioning p53 protein. An extreme case of this is Li Fraumeni syndrome, where a genetic a defect in p53 leads to a high frequency of cancer in affected individuals. A genetically-engineered adenovirus, called ONYX-015, can only replicate in human cells lacking p53. Thus it infects, replicates, and ultimately kills many types of cancer cells in vitro. Clinical trials are now proceeding to see if injections of ONYX-015 can shrink a variety of types of cancers in human patients.

Variations within different cells

The human body contains a huge range of cells ~ over 300 different types. The fastest cycling mammalian cells in culture, crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. cells are most radiosensitive in late M and G2 phases and most resistant in late S. Some divide often through life, others divide only infrequently and some do not divide at all after birth. The most actively dividing cells are found in areas of the body that receive a lot of wear and tear.(skin,GIT) Liver tissue is very interesting. it is usually permanent but when massive damage to the liver occurs, the cells can get out of G0 and undergo mitosis to repair the tissue

Why do nerve cells dont divide?

For any animal cell to divide, spindle-like structures have to be formed by the centrosome, which in its turn is formed by the chromatin granules if and only if all these granules remain within the nucleus. But in nerve cells, some of these granules remain scattered in the cytoplasm outside the nucleus. As they are found outside the nucleus, they cannot form the centrosome and as such no spindle fibres. Hence, unlike most animal cells, nerve cells or neurones, as they are otherwise known, generally don't divide. It is the connection between them that matters the most .Over the time these connections form making memeories storing information, their division will put extra strain in making these connections.Also new cells cannot be made useful without years of connection forming exercise .It has do with the way neural networks learn.It is better to use existing neurons and make new connections and pathwyas rather than making new cells and start from scratch each time.

Applied physiology
Deregulation of cell cycle control proteins plays a key role in the development of cancer.

Overactivation of proteins that favor cell cycle progression, namely cyclins and CDKs, and the inactivation of proteins that impede cell cycle progression, such as CKIs, can result in uncontrolled cell proliferation.

ATM
ATM (="ataxia telangiectasia mutated") gets its name from a human disease of that name , whose patients are at a greatly increased (~100 fold) risk of cancer. The ATM protein is involved in detecting DNA damage, especially doublestrand breaks; interrupting (with the aid of p53) the cell cycle when damage is found; Maintaining normal telomere length. It is a rare, neurodegenerative, inherited disease that affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease.

Telomere and Telomerase

Telomeres, located at the ends of chromosomes, are key genetic elements involved in the regulation of the cellular aging process. E ach time a normal cell divides, telomeres shorten. Once telomeres reach a certain short length, cell division halts and the cell enters a state known as replicative senescence or aging. Thus, this shortening of the telomeres effectively serves as a molecular "clock" for cellular aging. when the enzyme telomerase is introduced into normal cells, it can restore telomere length - reset the "clock" - thereby increasing the functional lifespan of the cells. Importantly, it does this without altering the cells' biology or causing them to become cancerous.

Telomerase
Human telomerase present at very low levels, in most normal cells and tissues, but that during cancer progression, telomerase is abnormally reactivated in all major cancer types. while telomerase does not cause cancer, the continued presence of telomerase enables cancer cells to maintain telomere length, providing them with indefinite replicative capacity. It has been shown in various tumor models that inhibiting telomerase activity results in telomere shortening and causes aging or death of the cancer cell. Development of anti-cancer therapies based on telomerase inhibitors and telomerase therapeutic vaccines

Telomere and Telomerase

CANCER TREATMENT
Chemotherapy of cancers is aimed towards interrupting the cell cycle and preventing the cancer cells from proliferating. As a side effect, however, also the normal sites of cell proliferation are affected resulting in hair loss, intestinal disorders, anaemia and infertility.

Anticancer drugs
Some cytostatic drugs act on the S phase and inhibit DNA synthesis Methotrexate Fluorouracil Mercaptopurine Some cytostatic drugs cause cells to accumulate in G2 Mitomycin C Adriomycin Cyclophosphamide

ANTICANER DRUGS
VINCA ALKALOIDS(mitotic inhibitors)
Vincristine Vinblastin (bind to the microtubular protein TUBULIN and prevents its polymerization,disruption of cyotoskeleton)

PACLITAXELS(Disturbs the tubulin microtubule

dynamic equilibrium) Paclitaxel Docetaxel

Psoriasis
rapid proliferation of skin cells, which divide up to 1,000 times faster than normal. In normal cells, high cGMP levels makes cells divide faster, while high cAMP levels slow down cell division. Individuals with psoriasis have both high cGMP and low cAMP levels, causing the cells to replicate abnormally fast. This imbalance results in a tremendous increase in cell division.

REFERENCES
THE CELL- Geoffrey. M .Cooper Molecular Biology Of CellBruce,Alexender,Lewis,Marin,Roberts,Peter GRAYS Human Anatomy HUMAN physiology-FOX HUMAN PHYSIOLOGY-Rhoades Internet

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