Plugs are Cyclin – Cdk inhibitory proteins. There are also cyclin removing enzymes.
The brain doesn’t divide but does have APC/C to remove cyclin B1 that might appear there by
accident. In this way, mitosis is evaded in brain cells.
G1 → S phase transition = positive feedback loop (cyclinD-CDK4 phosphorylates pRB which induces
the production of Cyclin E → binds to CDK2 and also phosphorylates pRB = positive feedback).
Genotoxic/oncogene stress → p53 → p21 binds to cyclinE-CDK2 → active Rb → no active E2F → no
more cyclin E produced → cell cycle arrest in G1.
Cyclin D → after a growth factor signal. In case of cancer it is already there and all cells can go into
the cell division cycle. This results in cell growth = cancer.
Mitotic spindle checkpoint = internal checkpoint, DNA damage checkpoints = external checkpoints.
Down’s syndrome = there is one chromosome pair that didn’t align in the middle but the cell already
divides so one cell has extra and one cell has too less so that one dies and the other cell divides
further with the wrong amount of chromosomes. This can only happen with chromosome pair 21.
For almost every other chromosome pair it would be lethal.
Lecture 6 The p53 Pathway
Job de Lange
P53 is a direct target of several viral oncoproteins. Germline TP53 mutation underlie the cancer-
prone Li-Fraumeni Syndrome.
MDM2 knockout mice is embryonic lethal, but when they’re also P53 knockout, they will survive but
will develop tumors.
P53 is regulated by MDM2 and Mdmx. MDM2 controls p53 protein levels through continuous poly-
ubiquitination. Mdmx can help MDM2 to be more efficient. MDM2-Mdmx heterodimer is more
effective than the MDM2-MDM2 homodimer. Mdmx also blocks p53 activity.
The brain doesn’t divide but does have APC/C to remove cyclin B1 that might appear there by
accident. In this way, mitosis is evaded in brain cells.
G1 → S phase transition = positive feedback loop (cyclinD-CDK4 phosphorylates pRB which induces
the production of Cyclin E → binds to CDK2 and also phosphorylates pRB = positive feedback).
Genotoxic/oncogene stress → p53 → p21 binds to cyclinE-CDK2 → active Rb → no active E2F → no
more cyclin E produced → cell cycle arrest in G1.
Cyclin D → after a growth factor signal. In case of cancer it is already there and all cells can go into
the cell division cycle. This results in cell growth = cancer.
Mitotic spindle checkpoint = internal checkpoint, DNA damage checkpoints = external checkpoints.
Down’s syndrome = there is one chromosome pair that didn’t align in the middle but the cell already
divides so one cell has extra and one cell has too less so that one dies and the other cell divides
further with the wrong amount of chromosomes. This can only happen with chromosome pair 21.
For almost every other chromosome pair it would be lethal.
Lecture 6 The p53 Pathway
Job de Lange
P53 is a direct target of several viral oncoproteins. Germline TP53 mutation underlie the cancer-
prone Li-Fraumeni Syndrome.
MDM2 knockout mice is embryonic lethal, but when they’re also P53 knockout, they will survive but
will develop tumors.
P53 is regulated by MDM2 and Mdmx. MDM2 controls p53 protein levels through continuous poly-
ubiquitination. Mdmx can help MDM2 to be more efficient. MDM2-Mdmx heterodimer is more
effective than the MDM2-MDM2 homodimer. Mdmx also blocks p53 activity.
