Topic 10: cell cycle regulation Flashcards
Define cancer
- Abnormal cell growth = proliferates uncontrollably = metastasize
Define malignancy
- Tumor property = invade nearby tissue + spread to other part
How many types of cancer are there?
- At least 200
What are the cancers with the highest incidence?
1) Breast
2) Lung
3) Colorectal
What is the cancer mortality in 2020?
- Almost 10 million deaths
Define carcinogenesis
- Cell with mutations
- Activation of oncogenes + inactivation of tumor suppressor genes = uncontrolled cell division + defective apoptosis pathway = cancer
Describe the variations in cell types
- Skin = frequently + throughout life
- Liver = ability to divide in response to specific need
- Nerve = don’t divide in mature humans
- Differences result from = regulation at molecular control system
3 Checkpoints for cell cycle regulation
1) G1
2) G2
3) M
Describe G1 checkpoint
- At end of G1 = checks for growth factors + cell size + DNA damage
- Controls transition to S phase DNA replication
Describe G2 checkpoint
- Checks for DNA damage + completion of DNA replication
- Controls transition to M phase mitosis
Describe M checkpoint
- Controls transitions through stages of mitosis
- Makes sure correct chromosome alignment in mitotic spindle
Describe what happens if damage is detected at a checkpoint
- If damage detected at G1/G2 = cell cycle arrest
- Attempt to repair DNA damage
- If not possible = apoptosis
What are the components of cell cycle control?
- Maintained by protein complexes with 2 subunits =
1) Cyclin = regulatory subunit
2) Cyclin depended kinase = catalytic subunit - Kinase = enzymes that activate/inactivate other proteins by phosphorylation
Explain CDK activity
- Regulated by degradation of cyclins proteasomes
- Proteasome = giant protein complex = binds to short lived proteins = degrades them
- Proteins that will be degraded = marked by ubiquitin via enzyme = ubiquitin ligases
Describe regulation during mitosis
- Signal to send cells into mitosis = MPF
- MPF = 1st CDK to be discovered
- MPF = mitotic cyclin = cyclin A/B + CDK-1
- MPF induces G2 > M = phosphorylation of proteins in nuclear lamina = fragmentation of nuclear envelope
Describe the negative regulation of MPF
- APC = inactivates mitotic cyclin = inactivates MPF
- Proteolysis of mitotic cyclin at end of mitosis = reduces MPF activity
What are the roles of MPFs?
- Chromosomal condensation
- Nuclear envelope degredation
- Mitotic spindle formation
- Chromosome migration
- Organelle reformation
- Cytokinesis
Describe regulation during interphase
1) Mitogen growth factors = external signals stimulate cell division = trigger pathways
2) Expression of early response genes =
- G1 cyc-cdk = cyc-D/E + cdk 2/4/6
- Transcription factors = c-Fos + c-Jun+ E2F
3) Activation of G1 cyc-cdk activity =
- Cyc D-cdk4/6 + cyc E-cdk2 complexes become active = phosphorylate Rb = inactivation
- Inactivated Rb = releases E2F = drives transcription
4) Transcription of genes for DNA synthesis = E2F promotes transcription of DNA synthesis genes needed in S phases
What happens if mitogen is removed?
- Reduced cyc-cdk levels
- Cells don’t pass through G1 restriction point
- Cells don’t replicate
What are the cyc-cdk complexes at each checkpoint?
- G1 = cycD-cdk4/6 + cycE-cdk2
- S = cycA-cdk2
- M = cycA/b-cdk1 + MPF
Define tumor suppressor genes
- The protein products of TSG = inhibit cell division = prevent uncontrolled growth
- RB1 + TP53 = proteins Rb + p53
Define retinoblastoma protein
- Tumor suppressor gene = codes for tumor suppressor protein
- Sequesters = binds to transcription factor E2F = inhibits activation
Describe regulation of Rb
- G1 phase = Rb dephosphorylated by PP-1
- End of G1 = cyc-cdk phosphorylate Rb = cannot sequester E2F
- E2F released = activated = cell enters S phase
Describe retinoblastoma
- Malignant tumor in eyes = originates from retina
- Cause = mutation in RB1 tumor suppressor
- Can be uni/bilateral
- Affects typically children under 5
- 2 types = familial/sporadic
Describe the negative regulators of the cell cycle
- Cdk inhibitors = CKI = inhibit cyc-cdk complexes
- 2 types:
1) INK4 family = inhibit G1 cyc-cdk - P15INK4b
- P16INK4a
- P18INK4c
- P19INK4d
2) Cip/Kip family = inhibit all other cyc=cdk - P21Cip1
- P27Kip1
- P57Kip2
- Expression stimulated by DNA damage = p53 activation
Explain how CKIs work
- DNA damage > inducer p53
- Triggers CDK inhibitor = CKI = inhibits CDK kinase activity
- Therefore cell cycle arrest
Explain the activation of p53 in response to DNA damage
- DNA > mutation > DNA damage > activates p53
- Initially p53 = inactive + degraded by proteasome
- Damage = kinase activation = phosphorylates p53 = activates p53
- Once activated = 3 pathways
1) Cell arrest = increase expression of CKI
2) DNA repair = excision repair to normal
3) Apoptosis = damage to severe
Describe the TP53 gene
- The guardian of the genome
- Encodes for p53
- Over 50% cancer = mutation in TP53 = most commonly affected tumor suppressor gene
Describe the function of p53
- Detects DNA damage
- Induces G1-G2 cell cycle arrest
- Induces apoptosis
Define internal signals
- Cell size
- Incorrect alignment
- Separation of sister chromatids before time
Define external signals
- Environmental conditions
- Presence of growth factors
Define PDGF
- Stimulates fibroblasts growth in wound/culture
Describe the experiment with PDGF
1) Sample of connective tissue cut up
2) Enzymes used to digest ECM = suspension of free fibroblast cells
3) Cells transferred = sterile culture vessels = basic growth medium = glucose + amino acids + salt + antibiotics
- PDGF added to 1/2 vessels = culture incubated 37°C
Describe the 2 external signals as a result of the experiment
1) Density-dependant inhibition:
- Crowded cells stop dividing
- Cells form single layer = stop dividing g
- If cells removed = cells divide to fill gap then stop
2) Anchorage dependence:
- Cells need to be attached to support to divide
- Cells anchor to dish surface = divide
Describe the transformation of normal cell > cancer cell
- No density dependant inhibition + anchorage dependence
- Cancer cells divide over single layer = overlap
Describe the loss of cell cycle control in cancer cells
- Make own growth factors
- Have signaling pathways always ON
- Abnormal cell cycle control = form tumors
Define the 2 types of tumors
1) Benign = non-invasive + contained to a particular site
2) Malignant = invasive + spread to other organs
Describe malignant tumors
1) Tumor grows from singular cell
2) Cells invade neighboring tissue
3) Cells spread via lymph/blood vessels = other parts of body
4) If cancer cells survive = form secondary tumor in new part of body
What are the characteristics of cancer cell?
- Resisting cell death
- Sustaining proliferative signaling
- Evading growth suppression
- Activates invasion/metastasis
- Replicative immortality
- Induces angiogenesis
Define precision oncology
- Using a patient’s genetics = create treatment plans targeted to molecular characteristics of their cancer
