Chapter 12 (cont.) - cell cycle regulation and cancer

What does the G₁ checkpoint look for?

• Cell size adequate (large enough)

• nutrients are sufficient

• social signals are present

• DNA is undamaged

If a cell does not pass the G₁ checkpoint where does it go?

G₀ - “sent into retirement”

• No more cell division

How do cells enter G₀

• Do not pass G₁ checkpoint

• Once cell has gone through “max” cell divisions in lifetime will retire

What does the G₂ checkpoint look for?

• If chromosomes have replicated successfully

• If DNA is damaged

What does M-phase checkpoints look for?

• If chromosomes have attached to spindle apparatus (pro-metaphase → metaphase)

• If chromosomes have properly segregated

Cyclins

Only produced when needed

• Different types for different phase transitions

  • G₁, G₁/S, S, and M

Cdks

• an enzyme that attaches phosphate groups to other proteins

• Cyclin dependent kinases

• when paired together with a cyclin, ativate other proteins to progress the cell cycle

M-phase-promoting factor (MPF)

Cycle cycle protein that tells a cell to go into M phase (in cytoplasm)

• Made up of Cyclin B + CDK1

Steps:

• Interphase

• G2 checkpoint

• M-phase checkpoint

What stops Cdk from being prematurely active?

It has an additional phosphate group on it that keeps it from doing its job

How is the Cdk affected by the G₂ checkpoint (regulation of MPF)

• Phosphatase removes inhibitory phosphate

• Cdk is active

How is M-phase checkpoint affect Cdk/cyclin? (Regulation of MPF)

• Cyclin is degraded

  • This causes Cdk1 to inactivate

What is the G₁ checkpoint controlled by?

1) Growth factors

2) Tumor suppressors

• p53 - DNA repair

• RB (pRB) - blocks transition from G₁ to S-phase

Growth factors

• Hormones (polypeptides or small proteins) that stimulate cell division

  • “gas” of the cell cycle (when they’re around the cell cycle moves forward/progresses)

Tumor suppressors

• proteins that restrict cell division

  • “brakes” of the cell cycle

What is the activator of S-phase?

E2F

• must be sequestered until cell is ready

Cancer

A collection of diseases caused by cells that:

• Divide in an uncontrollable fashion

• Invade nearby tissues

• spreads to other sites in the body

Tumor

Mass of cells

• even a single cell can begin to divide uncontrollably and form a tumor

Benign tumor

noninvasive and thus noncancerous

Malignant tumors

invasive and cancerous

Metastasis

spreading from a primary tumor site to establish secondary sites

Proto-oncogenes

Promote cell growth and division (ex. growth factors)

• when mutated become oncogenes

Oncogenes

an allele that promotes cancer development

• too much or “broken” proto-oncogene = cancer

Tumor suppressors

• Restrict cell growth and division

• removal of tumor suppressors = cancer

Mutations in Cancer?

• Typically 2-8 mutations found in tumor DNA

• Typically 1+ oncogene and multiple tumor supressors

Genetic predisposition

• Increased likelihood of developing a particular disease based on a person’s genetic makeup

  • Often abnormal (mutant) copy of a tumor-suppressor gene

Carcinogen

Any substance that promotes cancer

• Tobacco

• Acetaldehyde

• UV light

• Outdoor air pollution

Why is cancer so difficult to cure

• Cancer is not one disease, but many

  • No singular cure for a group of diverse disorders

• Difficult to target only cancerous cells

• New and rare cancers are appearing frequently

Explain CDK and Cyclin concentrations in this image

CDKS are always around

• Constant concentration at all times

• Only active when cyclin is attached

What happens with CDK and Cyclin in interphase (Regulation of MPF)

Cyclin B builds up and binds to CDK

• CDK inactive due to inhibitory phosphate

Rb role?

Inactivates E2F by binding to it

How its removed:

• After idk phosphorylates Rb after inactivating phosphate is removed from cdk/cyclin

• Phosphorylated Rb releases E2F

What are some defects that can occur in the control of the G1 checkpoint pathway that can lead to cancer?

• Too much growth factor - too much cyclin/E2F

  • Too much E2F to hold back → unwanted S phase

• No Rb

• Too much phosphatase- if phosphate removed early -> premature phosphorylating Rb → premature phase

• Too much E2F

Cyclin-dependent kinase (Cdk) is…

an enzyme that attaches phosphate groups to other proteins

A cyclin...

activates a Cdk molecule when it reaches a sufficient concentration