BIOL 313 | Ch13 - Molecular Genetics of the Cell Cycle and Cancer

The cell cycle is…

under genetic control

A fundamental feature of the cell cycle is that…

it is not reversible.

Pauses in the cell cycle occur at

cell cycle checkpoints

G0 Checkpoint

Cell waits for a certain amount of time to pass, or a certain amount of growth to occur, or an external signal such as a growth factor. Also seen at the ‘start’ of the cell cycle.

G2 Checkpoint

Cell waits while it checks its own health. Excessive DNA damage or protein misfolding will prevent passage of this checkpoint.

M Checkpoint

Cell waits for all chromosomes to attach to spindle fibers at metaphase

cyclins and cyclin-dependent protein kinases (CDK)

protein complexes are composed of these

kinase

an enzyme that adds phosphate groups to other molecules

Binding a cyclin.

Cdks are activated by this.

Cyclins are found

At various points in the cell cycle

transcription factor

A molecule that controls the activity of a gene by determining whether the gene’s DNA is transcribed into RNA

Cyclin B

A regulatory protein accumulates in G2 and activates a kinase.

Cdk (Cyclin-dependent kinase)

An enzyme activated by a regulatory protein to drive the cell cycle.

Transcription factors

Proteins that regulate gene expression for cell cycle progression.

Proteins that break down regulatory proteins to control the cycle

Proteins that degrade cyclins

Cdk activation

A kinase is activated to promote gene expression and degradation

Induces expression of cyclins D and E

Proper growth of the cell or activation of a growth factor receptor in G1

Retinoblastoma protein (RB)

Cyclins D and E activate Cdks that phosphorylate into this. Occurs in the G1 checkpoint.

E2F

A transcription factor released when RB is phosphorylated. Occurs in the G1 checkpoint.

E2F induces

expression of DNA polymerase and other replication proteins, as well as cyclins A and B.

“Restriction Point”

A nickname for the G1 checkpoint.

“DNA Damage”

A nickname for the G2 checkpoint.

p53

A transcription factor that blocks mitosis in the G2 checkpoint.

Cyclin B build up activates…

A Cdk that initiates mitosis

“Spindle assembly”

A nickname for the M checkpoint.

M checkpoint relies on…

protein degradation, and not protein expression

APC/C

(anaphase promoting complex) A ubiquitin ligase that marks securin for destruction

Securin

inhibitor of separase

separase

cleaves cohesions

cohesins

initiates anaphase

p53 is inhibited by

Mdm2

Mdm2 inhibits p53 by

binding it and transporting it to the proteasome

How do you phosphorylate and acetylate p53?

Damage DNA

A tumor supressor

p53

Activating p53 in the nucleus leads to

transcription of a variety of genes that prevent tumor development

What three things can genes do to prevent tumor development?

Cell cycle arrest, Inhibition of angiogenesis and metastasis, and Apoptosis

Apoptosis

Programmed cell death

Bcl2

Inhibitor of Bax

Bax

increased by p53 to induce apoptosis

Tumor suppressor gene

a gene that normally halts or controls cell cycle progression (or induces apoptosis)

Loss of function mutation

results in cancer

Oncogene

(proto-oncogene) a gene that normally promotes cell cycle progression (or prevents apoptosis)

Gain of function mutation

results in cancer

The accelerator getting stuck in a car causing a crash, is analogous to a _____ of function mutation in the _____.

gain, oncogene

The breaks going out in a car causing a crash, is analogous to a _____ of function mutation in the _____.

loss, tumor supressor gene

Loss of function mutations are

usually recessive

Gain of function mutations…

usually dominant

Familial mutation in the tumor suppressor RB leads to

retinoblastoma

Cancer is…

a variety of different combinations of genetic mutations that affect different types of cells

Philadelphia Chromosome

a chromosomal translocation that occurs in a specific location, swapping the tips of chromosomes 9 and 22 in 15-20% of leukemia cases.

Philadelphia Chromosome creates this

a chimeric fusion gene between the Bcr and the Abl gene

Abl gene

encodes a protein kinase that regulates blood cell development

Overactivity of Abl results in

overproduction of useless white blood cells and leukemia

Bcr-Abl

a uniquely shaped fusion protein only found in leukemia cells

Gleevec

A drug with Bcr-Abl fusion protein used to treat Chronic Myeloid Leukemia (CML)