Lecture 11: Cell Cycle 2

LOS: 1) The deregulation of the cell cycle in cancer (cyclin/cdk complexes) 2) control of cell cycle progression by extracellular signals and how this contributes to cancer

What does CDK stand for

cyclin dependent kinases

what is CDKs mechanism of action?

phosphorylation of downstream targets

What are CDKs/Cyclin complexes responsible for?

activating the proteins that carry the cells through the cell cycle

What happens if there is an abundance of cyclin subunits

cyclins activated the catalytic activity of the CDK partners (Cyclin A/CDK2 association increases CDK3 activity by 400,000)

How does cyclin/CDK association help with substrate recognition?

Type of cyclin bound determines which substrates are phosphorylated

Will phosphorylating cyclin-CDK complex inhibit them or activate them?

Can do both, depends on position of the phosphate molecule

How can phosphorylation deactivate a kinase

by binding to the ATP binding domain of the kinase

What does ubiquination of a cyclin-CDK complex cause?

Degradation of cyclin

What will happen if a CKI binds to a cyclin-CDK complex?

The complex will be inhibited

Describe cyclin levels as the cell progresses

rapid collapse of specific cyclin levels through ubiquitination-dependent degradation

What does the INK4 family do?

Inhibits D-CDK4/6

What does the Kip/ Cip family do?

Inhibits all CDKs apart from CDK 4/6

What stage is D-CDK4/6 associated with?

G1 (first 3 quarters)

What stage is E-CDK2 associated with?

late G1, early S

What stage is A-CDK2 associated with?

early S

What stage is A-CDC2 associated with?

Late S and G2

What stage is B-CDC2 associated with?

M

What happens when cyclin D1 is ectopically over expressed in pancreatic cancer cells?

Increased cell proliferation, increased anchorage-independent growth, reduced chemosensitivity and elevated survival in presence of chemo drug

What happened when ShCCND1 was injected in mice?

decreased tumour formation, induction of apoptosis

What does sShCCND1 do

partially reduces cyclin D1 protein expression

What was the correlation between cyclin D1 expression and survival

higher cyclin D1 expression was associated with lower survival rates in gastric cancer patients

What is cyclin D1 overexpression associated with?

increased invasion and metatastasis

Briefly outline cyclin Es role in cancer

E1 and E2 associate with CDK2 after R point, causing phosphorylation of substrates req. for S phase entry

What was the association between E1 and cancer?

overexpressed in 40% of ovarian high grade serum carcinomas (1/2 result of gene amp causing cell cycle prog. and res to therapy)

Where does HSOC originate

fallopian tube epithelium

What mutations are associated with HSOC

P53 mutations in early tumorogenesis

What is STIC in HSOC?

non invasive tumor, characterised by high proliferation

How is cyclin E1 an oncogene for ovarian cancer

Cyclin E1 overexpression promotes clonogeneic growth and contact inhibition loss

what are the two markers of ovarian cells?

Pax8 and CK7

What was the relationship between E1 overexpression and prognosis and why

correlation with poor prognosis

What was the association with cyclin E cleavage and cancer, why?

correlates with poor prognosis due to expression of lower mol weight cyclin E, stable protein with higher CDK2 affinity