Neoplasia

Tumor Suppressor Genes: Insensitivity to Growth Inhibition

Tumor suppressor genes
• Genes that encode for tumor suppressor proteins responsible for the
prevention of abnormal growth and proliferation of

Tumor Tumor Growth and

Suppressor Suppressor proliferation of
Genes Proteins cells
Tumor Suppressor Proteins
• May also function as:
• transcription factor
• cell cycle inhibitor
• signal transduction molecules
• cell surface receptors
• regulators of cellular response to DNA damage.
• Retinoblastoma (RB) Gene • NF1
• TP53 • NF2
• Adenomatous Polyposis Coli • WT1
(APC) Gene • PATCHED (PTCH)
• CDKN2A Gene • VHL
• TGF-B • STK11
• Phosphatase and Tensin
Homologue (PTEN)
Tumor Suppressor Genes
RB (Retinoblastoma) NF1
TP53 NF2
APC (Adenomatous Polyposis WT1
Coli)
CDKN2A PTCH (PATCHED)
TGF-β VHL (Von Hippel-Lindau)
PTEN (Phosphatase and STK11 (LKB1)
tensin homologue)
Knudson’s “Two-Hit”
Hypothesis of
Oncogenesis

Both alleles are

required to have
both the mutation
in order to form
cancer
Acquired knowledge about cancers through the
study of retinoblastoma gene:

• autosomal dominant

• Tumors acquire a second hit in the normal tumor suppressor gene

allele

• The same tumor suppressor gene is frequently mutated in sporadic

tumors of the same type.
Retinoblastoma (RB) Gene
• First TSG discovered
• Key negative regulator of the G1/S cycle transition
• Carriers have 10,000-fold increased risk of developing retinoblastoma
• Locus: 13q14
Familial Sporadic
Percentage of total 40% 60%
population with
retinoblastoma
Risk of developing Yes No
osteosarcoma and other
soft-tissue sarcomas?
Retinoblastoma (RB) Gene
Retinoblastoma (RB) Gene
• DNA viruses neutralize the growth-inhibitory activities of RB by
binding to the hypophosphorylated RB:

• Simian virus 40
• Polyomavirus large T antigens
• Adenovirus EIA protein
• HPV E7
Key regulators of cell cycle
• P16/INK4a
• Cyclin D
• CDK4
• RB
Gene Protein Chromosome Function Familial Syndromes Sporadic Cancers

RB Retinoblastoma 13q14 Inhibitor of G1/S Familial Retinoblastoma;

(RB) protein transition during retinoblastoma osteosarcoma
cell cycle syndrome carcinomas of
progression (retinoblastoma, breast, colon, lung
osteosarcoma,
other sarcomas)
TP53 P53 protein 17p13.1 Cell cycle arrest and Li-Fraumeni Most human
apoptosis in syndrome (diverse cancers
response to DNA cancers)
damage
APC Adenomatous 5q21 Inhibitor of WNT Familial colonic Carcinomas of
polyposis coli signaling polyos and stomach, colon,
protein carcinomas pancreas;
melanoma
CDH1 E-cadherin 16q Cell adhesion, Familial gastric Gastric carcinoma,
inhibition of cell cancer lobular breast
motility carcinoma
CDKN2A P16/INK4a and P16: Negative Familial melanoma Pancreatic, breast,
p14/ARF regulator of cyclin- and esophageal
dependent kinases; carcinoma,
p14, indirect melanoma, certain
Gene Protein Chromosome Function Familial syndromes Sporadic cancers

SMAD2, SMAD4 SMAD2, SMAD4 Component of the Juvenile polyposis Frequently mutated
TGF-B signalling (along with other
pathway, components of the
repressors of MYC TGF-B signalling
and CDK4 pathway) in colonic
expression, and pancreatic
inducers of CDK carcinoma
inhibitor expression

PTEN Phosphatase and 10q23 Inhibitor of Cowden syndrome Diverse cancers,

tensin homologue PI3K/AKT signalling (variety of benign particularly
skin, GI, and CAN carcinomas and
growths; breast lymphoid tumors
endometrial, and
thyroid carcinoma)
NF1 Neurofibromin-1 Inhibitor of Neurofibromatosis Neuroblastoma,
RAS/MAPK type 1 juvenile myeloid
signaling (neurofibromas and leukemia
malignant
peripheral nerve
sheath tumors)
Gene Protein Chromosome Function Familial syndromes Sporadic
carcinomas

NF2 Merlin Cytoskeletal Neurofibromatosis Schwannoma,

stability, Hippo type 2 (acoustic meningioma
pathway signaling schwannoma and
meningioma)
WT1 Wilms tumor-1 11p3 Transcription factor Familial Wilms Wilms tumor,
(WT1) tumor certain leukemias

PTCH Patched Inhibitor of Gorlin syndrome Basal cell

Hedgehog (basal cell carcinoma,
signalling carcinoma, medulloblastoma
medulloblastoma,
several benign
tumors
VHL Von Hippel Lindau 3p Inhibitor of Von Hippel Lindau Renal cell
(VHL) protein hypoxia-induced syndrome carcinoma
transcription (cerebellar
factors (e.g. HIF1a) hemangioblastoma,
retinal angioma,
renal cell
carcinoma)
Genes Proteins Chromosome Function Familial Syndromes Sporadic
carcinomas

STK11 Liver kinase B1 Activator of AMPK Peutz-Jeghers Diverse carcinomas

(LKB1) or STK11 family of kinases; syndrome (GI (5%-20% of cases,
suppresses cell polyps, GI cancers, depending on type)
growth when cell pancreatic
nutrient and carcinoma and
energy levels are other carcinomas)
low
TP53 Gene
• Encodes the protein p53
• Regulates:
• Cell cycle progression
• DNA repair
• Cellular senescence
• Apoptosis

• Most frequently mutated gene in human cancers, found in >50% of

cancers
TP53 Gene
• Li-Fraumeni syndrome patients have 25-fold greater chance of
developing a malignant tumor by age 50.

• MDM2 enzyme ubiquinylates p53, stimulating its degradation.

TP53
P53 is released due to
• 1. DNA damage and hypoxia
• Protein kinase key initiators after DNA damage or hypoxia:
• Ataxia-Telangiectasia mutated (ATM)
• Ataxia-Telangiectasia and Rad3 related (ATR)
-phosphorylates p53 and MDM2, allowing p53 to accumulate

• 2. Oncogenic stress
Target genes of p53
• Genes that:

• 1. cause cell cycle arrest

• 2. cause apoptosis
• 3. enhance catabolism or inhibit anabolism
• 4. encode micro-RNA (mIRs) and long intervening noncoding (LINC)
RNAs, regulatory RNAs
Accumulation of p53 results to
1. Cell cycle arrest
-occurs late in G1 phase
-transcription of CDKN1A
-induces GADD45 (growth arrest and DNA damage)

• 2. Senescence
-permanent cell cycle arrest

• 3. Apoptosis
-transcription of pro-apoptotic genes: BAX and PUMA
APC (Adenomatous polyposis coli)
• Located at chromosome 5q21
• Downregulates growth-promoting signalling pathways

• LOF mutation: Familial denomatous polyposis

-development of thousands of adenomatous polyps in the
colon during teen age or 20s
APC Gene
• 70%-80% of nonfamilial colorectal carcinomas and sporadic
adenomas show defects in APC

• GOF mutations in B-catenin are present in

>50% of hepatoblastomas
app. 20% of hepatocellular carcinomas
APC
CDH1
• Codes for E-cadherin
• Cell surface protein maintaining intercellular adhesiveness
• Where B-catenin is bound
TGF-B Pathway
Turns on
antiproliferative
genes

Intracellular
TGF-B I and II Receptor
TGF-B signals involving
receptors dimerization
SMAD family

Turns off genes

that drive cell
growth
PTEN (Phosphatase and tensin homologue)
• Membrane-associated

• Brake on the P13K/AKT arm of receptor tyrosine pathway

• Mutated in Cowden syndrome

-Frequent benign growths: skin appendage tumors, increased
incidence of epithelial cancers (breast, endometrium, and
thyroid)
NF1
• One mutant allele: numerous benign neurofibromas and optic nerve
gliomas (neurofibromatosis type 1)
NF2
• Somatic mutation: sporadic meningiomas and ependymomas
• Protein: Neurofibromin 2 or Merlin –structurally similar to RBC
membrane cytoskeleton protein 4.1 and is related to ERM (erzin,
radixin, and moesin) family of membrane cytoskeleton-associated
proteins
WT1
• Regulates mesenchymal-to-epithelial transition in kidney
development

• Wilms tumor-pediatric kidney cancer

• Overexpressed in leukemias and breast caner carcinomas (oncogene)

PATCHED (PTCH)
• Half mutations in BCC are type caused by UV exposure
• Sporadic: 20 to 50% of BCC
• 10 to 25% of medulloblastoma
VHL
• Component of ubiquitin ligase
• -hypxia: hydroxylation reaction does not occur, and HIF1a escapes
recognition by VHL -> HIF1a accumulates in the nuclei of hypoxic cells
and turns on many target genes: genes encoding the
growth/angiogenic factors vascular endothelial growth factor (VEGF)
and PDGF, the glucose transporter GLUT1, and several glycolytic
enzymes.
• -loss-of-function mutation also prevents ubiquination even in
normoxic conditions
STK11 (LKB1)
• -encodes a serine/threonine kinase, a regulator of cellular
metabolism
-loss-of-function mutations: Peutz-Jeghers syndrome, autosomal
dominant associated with benign polyps of the gastrointestinal tract
and increased risk of multiple epithelial cancers, particularly
gastrointestinal and pancreatic carcinomas.
• -sporadic mutations: loss-of-function mutations in diverse carcinomas
Warburg Effect
• Aerobic glycolysis
Autophagy
• Cells consume their own organelles, proteins, and membranes for
energy production

• Tumors use this when they are nutrient-deprived to become

“dormant” to be able to survive.
End