P53, Apoptosis, Cancer, More Regulation

G1 checkpoint

• Controlled by G1 Cdk-cyclin

• G1 cyclin levels also vary with the cell cycle

• Many additional levels of phosphorylation, dephosphor-ylation regulate.

P

Cyc D

cdk4

pRBE2F

E2FE2F

E2F P

PP

P

E2F E2FE2F E2F

Cyc E

cdk2

Growth Factor Signaling Through the Ras Pathway crossing of G1 checkpoint

Ras*, Raf*

MAPKcascade

Activation of nuclear TFs

Activation of G1 Cdk cyclin genes: G1 S

G2 Checkpoint Control by MPF

• Active MPF = Mitotic Cdk + mitotic cyclin• Cdk is cyclin-dependant kinase• MPF controls G2 M by phosphorylating and

activating proteins involving in:– Chromosome condensation– Nuclear envelope breakdown– Spindle assembly– It’s own self-destruction

G2 checkpoint

Sister chromatid separation from prometaphase to anaphase

Securin

Separase

Cohesin

metaphase

Securin

Separase

Cohesin

prometaphase

APC

Check

point

Separase

APC

Securin

Separase

anaphase

Check

point

Spindle Assembly Checkpoint Controls Metaphase Anaphase

• MPF (+) anaphase promoting complex, which destroys:

1. Securin, which allows separin protease to cleave cohesin.

2. Mitotic cyclin, which causes loss of MPF activity, leading to chromosome decondensation and envelope reformation.

(+)

Section 20.2: Control of Mitosis by Cyclins and MPF Activity

Maturation promoting factor (MPF) is a protein kinase (requiring a mitotic cyclin) that stimulates mitosis, and hence is also called mitosis promoting factor.

The increase and decrease in MPF activity during the cell cycle in the early embryo reflects the cyclic synthesis and degradation of mitotic cyclins.

The anaphase-promoting complex/cyclosome (APC/C) is a ubiquitin ligase that recognizes the destruction box sequence in mitotic cyclins, marking them for degradation in late anaphase and thus terminating mitosis.

Deactivation of APC/C (by G1-cyclin/CDK) in G1 permits mitotic (and S phase) cyclins to accumulate, allowing the cell cycle to continue.

DEF: A gene which encodes a protein that regulates all growth and is able to cause potential cancerous cells to destroy themselves. The gene is an antioncogen.

F(x): Includes regulation of critical cellular function involving the G1 and G2 cell-cycle check points in response to DNA damage and apoptosis induced by certain stimuli, such as DNA damaging agents and hypoxia.

Additional F(x): The tumor suppressor gene functions as the “guardian of the genome” plays a pivotal roe in “sending” damaged DNA and in making critical decisions of whether a cell should repair the damaged DNA.

The tumor suppressor gene p53 is located at chromosomes region 17p13 and is one of the most frequently mutated gene in human cancers.

APOPTOSIS

Programmed cell death

Orderly cellular self destruction

Process: as crucial for survival of multi-cellularorganisms as cell division

• Important in normal physiology / development– Development: Immune systems maturation,

Morphogenesis, Neural development– Adult: Immune privilege, DNA Damage and wound repair.

• Excess apoptosis– Neurodegenerative diseases

• Deficient apoptosis– Cancer– Autoimmunity

IMPORTANCE OF APOPTOSIS

STAGES OF CLASSIC APOPTOSISHealthy cell

DEATH SIGNAL (extrinsic or intrinsic)

Commitment to die (reversible)

EXECUTION (irreversible)

Dead cell (condensed, crosslinked)

ENGULFMENT (macrophages, neighboring cells)

DEGRADATION

APOPTOSIS: Role in Disease

TOO MUCH: Tissue atrophy

TOO LITTLE: Hyperplasia

NeurodegenerationThin skin

etc

CancerAthersclerosis

etc

APOPTOSIS: Role in Disease: Cancer

Apoptosis eliminates damaged cells(damage => mutations => cancer

Tumor suppressor p53 controls senescenceand apoptosis responses to damage

Most cancer cells are defective in apoptotic response(damaged, mutant cells survive)

High levels of anti-apoptotic proteinsor

Low levels of pro-apoptotic proteins===> CANCER

OPTIMAL FUNCTION (HEALTH)

APOPTOSIS

APOPTOSIS

AGING

Neurodegeneration, cancer, …..

P53 & Apoptosis

p53 first arrests cell growth between G1 S

This allows for DNA repair during delay

If the damage is too extensive then p53 induces gene activation leading to apoptosis (programmed cell death)

Cancer: Benign

• Benign: localized and of small size

• Cells that closely resemble, and may function, like normal cells

• Become problems due to sheer bulk or due to secretions (e.g. hormones)

Malignant tumors: high rate of division, properties may vary compared to cells of origin. Most malignant cells become metastaticInvade surrounding tissue and establishment of secondary areas of growth: Metastasis

Cancer : Malignant

MetastasisCarcinoma: derived from endoderm or ectoderm

Events in metastasis.

Cancer has a lot to do with cell signaling for growth

Pathways leading to cancer