cancer 5 Flashcards
(17 cards)
π Whatβs the difference between oncogenes and tumor suppressor genes?
Tumor Suppressor Genes = Brakes on cell proliferation
Loss β uncontrolled growth
E.g. p53, Rb, p21
Oncogenes = Gas pedal for cell proliferation
Gain-of-function mutations β drive cancer
E.g. RAS, MYC, CDK4
𧬠Oncogene-induced senescence:
Oncogene in a normal cell β cell cycle arrest
Oncogene + missing tumor suppressor β tumor growth
π§ Oncogenes encode:
Growth Factors
RTKs (Receptors)
G-proteins (e.g. RAS)
Intracellular Kinases (e.g. BRAF)
Transcription Factors (e.g. MYC)
Cyclins & CDKs (e.g. Cyclin D, CDK4)
π Hallmark of cancer: Evading growth suppression (Hallmark #2)
π What are tumor suppressor genes and their functions?
π Tumor Suppressors = Genes/proteins that inhibit cancer hallmarks
Functions:
Block uncontrolled proliferation
Activate apoptosis pathways
Induce differentiation into non-dividing cells
𧬠Examples of tumor suppressor proteins:
Transcription factors: Rb
Cell cycle inhibitors: p16
Receptors: WNT
DNA damage response regulators: p53, BRCA1/2
π― End Result: Tumor suppressors limit or stop cell growth to prevent cancer.
What is the G1/S Checkpoint? and What Goes Wrong in Cancer?
This is a critical decision point in the cell cycle.
The cell decides whether to:
Enter S phase (DNA synthesis) and commit to division, or
Pause to repair or differentiate, or even undergo apoptosis.
HWOEVER
In nearly all cancers, the G1/S checkpoint is disabled. This means:
Cells keep entering S phase, even with DNA damage or no growth signals.
This leads to uncontrolled division and tumor growth.
Normal function of the Gβ/S checkpoint pathway
πΉ NORMAL Function:
Growth Factors (GF) bind to receptor tyrosine kinases (RTKs).
This activates RAS β stimulates MAPK and other pathways.
Leads to production of cyclin D, which activates CDK4/6.
Cyclin DβCDK4/6 phosphorylates Rb (Retinoblastoma protein).
Phosphorylated Rb releases E2F, a transcription factor.
E2F turns on S-phase genes β DNA replication begins.
πΉ Checkpoint Control:
p16 (from CDKN2A gene) inhibits CDK4 β keeps Rb active (unphosphorylated).
Unphosphorylated Rb holds back E2F β no S phase entry.
.
π₯ In Cancer: How g1/s Checkpoint Gets Deregulated
π΄ 1. Cyclin D Amplification
β More CDK4 activation β excessive Rb phosphorylation
β S-phase genes turned on constantly
Seen in: breast, oesophagus, liver, lymphomas
π΄ 2. CDK4 Amplification
β Same result: more Rb phosphorylation
Seen in: melanomas, sarcomas, glioblastomas
π΄ 3. Loss of CDKN2A (p16 loss)
β No inhibition of CDK4 β Rb gets phosphorylated even without signals
Seen in: pancreatic, esophageal cancers, glioblastoma
π΄ 4. Direct Rb Mutation
β Rb canβt bind E2F β E2F is always active
Seen in: retinoblastoma, other cancers
π΄ 5. Viral Oncoproteins
(From HPV, adenovirus) can bind and inactivate Rb directly.
CDKN2A function + cancer impact
gene that makes p16 and p14
p16 binds to cdk4 to prevent the formation of the cyclind-cdk4 complex, so Rb stays active and holds back E2F so no S-phase entry
p14 protects p53 by blocking MDM2 (a protein that degrades p53)
p53 == helps trigger cell cycle arrest or apoptosis if DNA is damaged.
If CDKN2A is mutated or silenced:
Both p16 and p14 are lost.
β Unregulated CDK4 (no p16)
β Unstable p53 (no p14)
Result: cells keep dividing, even with DNA damage.
What is NF1 (Neurofibromin-1) and β What Happens When NF1 Is Mutated?
RAS normally hydrolyses from GTP to GDP to keep itself in the inactive form
NF1 is a GTPase-activating protein (GAP).
It speeds up the conversion of RAS-GTP (active) to RAS-GDP (inactive).
Therefore, NF1 βturns offβ RAS faster β slows down cell proliferation.
This makes NF1 a tumor suppressor.
Without NF1:
RAS stays active longer (RAS-GTP is not hydrolyzed to RAS-GDP).
Constant signaling β continuous proliferation.
This uncontrolled growth can lead to tumors.
𧬠What is E-cadherin? and βοΈ How Does E-cadherin Control Cell Proliferation? and β In Cancer:
E-cadherin is a cell adhesion protein found in epithelial cells.
It helps cells stick together and plays a key role in contact inhibition β a natural stop signal when cells become crowded.
E-cadherin binds Ξ²-catenin at the cell membrane.
This prevents Ξ²-catenin from going into the nucleus.
If Ξ²-catenin stays out of the nucleus, it canβt activate cell cycle genes.
So:
β
E-cadherin present β Ξ²-catenin sequestered β no proliferation when cells touch.
β In Cancer:
E-cadherin is lost or mutated β Ξ²-catenin enters the nucleus.
Ξ²-catenin activates cell cycle genes β cells keep dividing, even when crowded.
This leads to the loss of contact inhibition β a hallmark of malignancy.
What is APC? βοΈ How APC Works Normally,
β What Happens When APC Is Lost?
APC (Adenomatous Polyposis Coli) is a tumor suppressor gene.
Its protein is part of the Ξ²-catenin destruction complex.
βοΈ How APC Works Normally:
APC binds Ξ²-catenin and helps form a destruction complex.
This complex tags Ξ²-catenin for degradation.
Result: Ξ²-catenin levels stay low β no activation of cell cycle genes.
β So, APC = βbrakeβ on Ξ²-catenin-driven growth.
β What Happens When APC Is Lost?
Ξ²-catenin is no longer destroyed.
It builds up and moves into the nucleus.
There, it activates genes that drive cell proliferation β uncontrolled growth.
difference between e-cadherin and apc
Both E-cadherin and APC help control Ξ²-catenin, but in different places and ways:
E-cadherin: At the cell membrane vs APC: In the cytoplasm
E-cadherin: physically binds Ξ²-catenin to keep it out of the nucleus vs APC: helps destroy free Ξ²-catenin (via destruction complex)
β In Cancer:
Loss of E-cadherin = Ξ²-catenin escapes the membrane
Loss of APC = Ξ²-catenin accumulates in the cytoplasm and enters the nucleus
Result: Uncontrolled activation of cell cycle genes β tumor growth
𧬠What is PTEN? (Phosphatase and Tensin homologue) β οΈ What PTEN Does:
β In Cancer: What Happens When PTEN Is Lost?
PTEN is a tumor suppressor gene.
It encodes a phosphatase that removes a phosphate group from PIP3, converting it back to PIP2.
This shuts down the PI3K/AKT pathway, which promotes cell survival and proliferation.
β οΈ What PTEN Does:
PTEN reverses PI3Kβs action:
Converts PIP3 back to PIP2.
Stops AKT activation.
Allows FOXO to remain active, promoting apoptosis or cell cycle arrest.
β In Cancer: What Happens When PTEN Is Lost?
No PTEN β PIP3 builds up.
β AKT stays active.
β FOXO stays off.
β Apoptosis is blocked, and cells proliferate continuously.
What Are BRCA1 and BRCA2?
BRCA1 and BRCA2 stand for Breast Cancer gene 1 and 2.
They are tumor suppressor genes.
Their proteins are involved in repairing double-stranded DNA, or kills damaged cells
β What Happens When Mutated?
DNA damage is not properly repaired.
Cells accumulate mutations β genomic instability β cancer develops.
𧬠What is p53?
π What Does Activated p53 Do?
β What Happens When p53 Is Lost or Mutated?
A tumor suppressor protein, encoded by the TP53 gene.
πΉ Under Normal Conditions:
p53 is kept inactive and degraded by MDM2.
πΉ Under Stress or DNA Damage:
ATM/ATR (DNA damage sensors) phosphorylate p53 β activates it.
p14^ARF (from CDKN2A) inhibits MDM2 β frees and stabilizes p53.
π What Does Activated p53 Do?
β
1. Cell Cycle Arrest (Transient):
Activates p21 (CDK inhibitor) β blocks CDK4/Cyclin D β keeps Rb active β blocks Gβ/S transition.
Allows time for DNA repair.
π§ 2. Senescence:
Permanent growth arrest (cells are alive but non-dividing).
π£ 3. Apoptosis:
If damage is beyond repair, p53 activates BAX and PUMA β triggers cell death.
DNA damage goes unchecked.
Cells accumulate mutations β become malignant.
what are the apoptosis pathways
Extrinsic Pathway: Who sends the death signal?
Signals (TNF or FasL) come from outside the cell, often from immune cells or the environment.
These bind to death receptors (like Fas or TNF receptor) on the cell surface β activate caspases β cell dismantles.
Intrinsic Pathway: How does it work?
Triggered by internal stress: DNA damage, Lack of survival signals, Oncogene activation, Hypoxia, oxidative stress
=> mitochondrial membrane becomes more permeable, releases cytochrome c, activates caspases, starts a cascade to kill the cell.
BCL-2 Family Proteins
gatekeepers of intrinsic apoptosis.
- Pro-survival= Keep mitochondria sealed e.g. BCL-2
- Pro-apoptotic = Create holes in the mitochondria e.g. BAX, BAK
- BH3-only = toward apoptosis (activated by p53)
e.g DNA is damaged.
p53 is activated β increases levels of BH3-only proteins.
BH3-only proteins:
Inhibit BCL-2 (pro-survival),
Activate BAX/BAK (pro-apoptotic).
Mitochondrial pores form β cytochrome c is released β apoptosis begins.
apoptosis pathways 𧬠In Cancer:
Apoptosis is blocked at multiple points so damaged cells wonβt die.
- Overexpression of BCL-2 (e.g., in lymphomas)
- Loss of p53 β no activation of pro-apoptotic proteins like PUMA
- Defects in death receptors or caspase function
==> Too much BCL-2 β blocks apoptosis
cancer cells survive and accumulate mutations
Replicative Immortality?
`
Normal human cells can only divide 60β70 times β this limit is called the Hayflick limit.
if Telomeres get too short, the cell triggers senescence
After that, they enter senescence, a permanent G1 cell cycle arrest in which they are alive but canβt divide.
Senescence== tumor suppressors (p53, p16, Rb etc) can block the G1/S checkpoint, preventing damaged or aged cells from dividing.
(cells now age but can no longer divide)
HWOEVER cancer cells are IMMORTAL:
. Mutate tumor suppressors (p53, Rb, p16) β escape senescence.
. Reactivate telomerase β gives them immortality (enzyme that extends telomeres (protective ends of chromosomes).)
