Lecture 12 - Cell cycle regulation Flashcards
What causes the cell cycle to progress?
Cyclins and Cdks
How ar4 Cdks regulated ?
- Cyclin binds to activate Cdks
- CKI protein (Cdk inhibitor). The cyclin when bound helps in substrate recognition.
- After one stage of the cell cycle specific cyclins collapse/ degrade in order to move cell cycle forward
CDK-CKI complex gets dephosphorylated in order to release CKIs so they can be active
What are the 3 types of CKIs
INK
CIP
KIP
they inactivate complexes when bound
What do CKIs do?
Bind to ATP binding domains of Cdks in order to inhibit the activity
What controls Cyclin D and where is it found in the cell cycle?
Cyclin D - controlled by ext enviroment of cell and specific molecules that activate and inhibit it are GFs and integrin-mediated ECM attachments
It is high in G1 phase and binds to Cdk 4/6. You need high levels of Cyclin D in order to move past the Restriction phase.
How does cyclin D contribute to cancer?
In cancer Cyclin D is always active in a cancer cell because there is impaired degradation of it.
You need Cyclin D to be expressed in order to have cancer. WT mice example
GFs needed for Cyclin D
When cyclin D1 os overexpressed = cell proliferation
underexpressed = reduces tumour growth
Gastric cancer
How does Cyclin E aide the cell cycle ?
Cyclin E - drives cell cycle into the S phase and binds to Cdk2
How does Cyclin E contribute to cancer?
Cyclin E allows clonogenic growth, and loss of contact inhibition as well (cells just grow on top of each other). Also promotes cell growth.
Cyclin E is overexpressed in ovarian cancer SGSC DUE TO GENE AMPLIFICATION that originates in the fallopian tube,
cancer starts with a p53 mutation
Associates with Cdk2
Cleavage of Cyclin E = higher affinity for Cdk2 = worse prognosis
What is TGFbeta and what does it do to cyclin D?
TGFbeta inhibits cell proliferation because it activates molecule p15INK4B
It decreases the level of cyclin D, so Cyclin D cannot form a complex with Cdk4/6 so it cannot go past the restriction point so there is no cell cycle.
In later stages contributes to tumour growth
What protein does TGFbeta weakly activate ?
TGFbeta weakly activates protein p21CIP1 (it’s a tumour suppressor, it stops the cell cycle to allow DNA repair)
Also activates the protein Transcription factors RSMAD
What is an Atg and what does it do?
Akt is an oncogene (in cancer always active).
It phosphorylates p21CIP meaning it leaves the nucleus and enters the cytoplasm so it cannot inhibit your Cdks.
It also phosphorylated p27KIP1 so it can’t go back into the nucleus
R point is between Cdk 4/6 and Cdk 2
Grwoth factors get rid of CKIS
