HRR: cell cycle Flashcards
what occurs in each step of interphase, generally
G1: metabolically active cells
S: DNA synthesis
G2: cell growth and preparation
what is G0?
Cells can exit G1 and enter G0, where they sit and wait to re-enter the cycle. They can re-enter in response to stimuli.
In what phase of the cell cycle do we find each cyclin
G1: D
S: E
G2: A
M: B
What are Cyclin-Dependent Kinases (CDK)
Enzymes that phosphorylate a large range of protein substrates (cyclins) required to complete the cell cycle. they bind cyclins to form active CDK/cyclin complexes. Their levels remain pretty constant during the cell cycle.
which cyclins and CDKs bind in G1
CDK4 or CDK6 and cyclin D
which cyclins and CDKs bind in the G1 to S transition
CDK2/cyclin E
which cyclins and CDKs bind in the S phase
CDK2/cyclin A
in S to G2 transition, which cyclins and CDKs bind
CDK1/cyclin A
in G2 to M transition, which cyclins and CDKs bind
CDK1/cyclin B
Describe maturation Promoting Factor (MPF)
It is the CDK1/cyclin B complex. It is a master regulator of the G2 to M transition, and it functions via phosphorylating proteins involved in mitotic processes
What are the major outcomes of maturation promoting factor
- Chromatin condensation
- Breakdown of nuclear envelope
- Formation of mitotic spindle
How do cyclins regulate CDK activity
Via fluctuation of the amount available; changes in its synthesis and degradation impact the amount of cyclin available to bind to CDK, regulating its action
Describe reversible phosphorylation of CDK/Cyclin Complexes
while cyclin binding CDK forms an active complex, sometimes phosphorylation is required. phosphorylation can further activate (CDK activating kinase) or inactivate (CDK inhibitory kinase) the complex, depending on where phosphorylation occurs.
Describe Cdc25 phosphatases
Cdc25 phosphatases activate the CDK/cyclin complex via dephosphorylation of the alternate sites
What are Cyclin-Dependent Kinase Inhibitors (CKI)
They bind to CDK/cyclin complexes and inhibit their activity. Growth factors regulate their levels.
what are the two big examples of CKI’s
p16 and p21
what does p16 do?
tumor suppressor gene that is a member of INK family that inhibits CDK4/cyclin D and CDK6/cyclin D and results in G1 arrest. Loss of this function enables the complexes to remain active
what does p21 do?
tumor suppressor gene that is part of the cip/kip family and inhibits CDK2/cyclin E and blocks G1 to S.
What is the G1 Restriction Point
A decision point that occurs in late G1; if a cell passes through this it is committed to S phase entry and completion of the cell cycle
What is Growth Factor Control
The presence of growth factors stimulates progression through G1 restriction point, while the absence of growth factors stops the cells at the restriction point, and they may enter G0
What in an example of a receptor activated by growth factors in the G1 checkpoint?
The EGF receptor (tyrosine kinase that initiates Ras-MEK-MAP kinase pathway)
Describe the EGF receptor in the context of the cell cycle
- Cyclin D is expressed
- Cyclin D binds CDK4 and CDK6, forming CDK/cyclin complexes
- Rb protein is phosphorylated by the complex and causes it to dissociate from E2F family of transcription factors
- E2F moves to nucleus and activates transcription of target genes required for cell cycle progression through G1 to S
E2F activates transcription of…
Cyclin E, cyclin A, DNA polymerase proteins
What are gain of function mutations
They result in a loss of cell cycle control due to unregulated progression through the G1 restriction point; often a product of oncogenes
What are the DNA Damage Control Checkpoints
They can arrest the cell cycle progression in response to DNA damage or unreplicated DNA; it is not the same as a restriction point
What is ATR
Kinase that is activated by single strand breaks, UV damage, or unreplicated DNA; phosphorylates CHK1, which phosphorylates cdc25 and prevents it from activating the CDK/cyclin complexes. This leads to inactivation of cyclins in the S phase and arrest of the cell cycle
What is ATM
Kinase activated by double strand breaks; phosphorylates CHK2, which phosphorylates cdc25 and inactivates it. This leads to inactivation of cyclins in the S phase and arrest of the cell cycle
Describe the role of Tumor Suppressor Genes
They encode proteins that function by regulating the cell cycle in response to things like DNA damage. Mutations to both copies of these genes can cause cellular transformation and lead to tumor development
What does tumor suppressor gene Rb do
Binds E2F and inhibits transcription of target genes; results in G1 arrest. this occurs when Rb is not phosphorylated
What does tumor suppressor gene p53 do?
the daddy of all tumor suppressor genes. ATM phosphorylates p53, which then produced p21. p21 will inhibit CDK2/cyclin E complex formation. this complex being blocks prevents phosphorylation of Rb, which effectively prevents G1 to S transition
