1) Tumor suppressor genes normally apply brakes to cell proliferation through proteins that form checkpoints to prevent uncontrolled growth. Loss of function of these genes allows tumor development.
2) The proteins encoded by tumor suppressor genes regulate cell cycle control, apoptosis, and cell survival/growth through mechanisms like transcription factors, cell cycle inhibitors, and DNA damage response.
3) Famous tumor suppressor genes include RB, p53, APC, and WT1. Mutation of both copies is required for loss of function, leading to cancers like retinoblastoma, Li-Fraumeni syndrome, colon cancer, and Wilms tumor.
MOTION MANAGEMANT IN LUNG SBRT BY DR KANHU CHARAN PATRO
Tumor suppressorgenes
1. Molecular Biology of Cancer -Molecular Biology of Cancer -
Tumor suppressor genesTumor suppressor genes
Dr.CSBR.Prasad, M.D.,
2. Failure of growth inhibition is one of
the fundamental alterations in the
process of carcinogenesis
3. • Oncogenes drive the proliferation of cells, the
products of tumor suppressor genes apply
brakes to cell proliferation
• The tumor suppressor proteins form a network
of checkpoints that prevent uncontrolled
growth
• Eg: RB and p53
– They are part of a regulatory network that
recognizes genotoxic stress from any source, and
responds by shutting down proliferation
6. Oncogene expression in an otherwise
normal cell leads to …….
Expression of an oncogene in an otherwise
completely normal cell leads to quiescence, or
to permanent cell cycle arrest (oncogene-
induced senescence), rather than uncontrolled
proliferation
7. In this class we will deal with…
• Tumor suppressor genes, their products, and
• Mechanisms by which loss of their function
contributes to unregulated cell growth
• The protein products of tumor suppressor
genes:
– Transcription factors
– Cell cycle inhibitors
– Signal transduction molecules
– Cell surface receptors, and
– Regulators of cellular responses to DNA damage
9. Tumor suppressor genes
• Physiologically they regulate cell growth
• It is a misnomer
• Failure of growth inhibition is key event in
carcinogenesis
• Loss of function of these genes - tumor
• The proteins that apply break to cell
proliferation are the products of these genes
10. Tumor suppressor genes
• Genes act by coding for growth controlling
molecules or growth factors
• Two pathways
– Control over mitosis
– Control over biochemical processes in the cell that
govern growth and differentiation i.e., gene
expression
11. Protein products of
tumor suppressor genes
• Cell cycle control
• Regulation of apoptosis
• Activities of cell survival and growth
12. Protein products of
tumor suppressor genes-function
• Transcription factors
• Cell cycle inhibitors
• Signal transduction factors
• Cell surface receptors
• Regulators of cellular response to DNA
damage
15. RB gene- two hit hypothesis
• Located on 13q14
• Both normal alleles must be inactivated (2- hits)
– First hit: Familial cases-born with one defective copy of
gene
– Second hit: The second intact copy undergoes somatic
mutation
• Sporadic cases-both normal RB alleles are lost by
somatic mutation in one of the retinoblasts
16.
17. RB Gene
• Familial RB show increased risk for
osteosarcoma & soft tissue sarcomas
• RB locus is seen in adenocarcinomas of breast,
small cell ca lung & bladder ca
• Alterations in “RB pathway” involving INK4a,
CDK’s, RB proteins are present in cancer cells
18. LOH- Loss of heterozygosity
• Child carrying inheritent mutant RB allele in all
somatic cells is perfectly normal, except for
increased risk for RB
• Child is heterozygous for the RB gene, which
does not affect cell behavior
• Cancer develops when cell becomes
homozygous for mutant allele
19. LOH- Loss of heterozygosity
• The cell loses heterozygosity for normal RB
gene (i.e., loss of heterozygosity)
23. RB protein
• Nuclear phosphoprotein, regulates cell cycle
• Active hypophosphorylated state in quiescent
cells
• Inactive hyperphophorylated state in G1/S cell
cycle transition
24. RB gene
• Regulates advancement of cells from G1/S
phase of cell cycle
• With RB mutation- transcription factor
regulation is lost- persistent cell cycling
• TGF b is a growth inhibiting cytokine that
upregulates CDK inhibitors, preventing
hyperphosphorylation
26. p53 gene
• Normal function- prevent propogation of genetically
damaged cells
• When DNA is damaged-p53 upregulation-
transcription of genes that arrest cell cycle and repair
DNA
• Cell cycle arrest is mediated by p53 dependent
transcription CDK inhibitor p21
• If DNA cannot be repaired, p53 induces apoptosis
27. Li-fraumeni syndrome
• High risk of developing carcinoma by
inactivation of 2 nd normal allele of somatic
cells
• Leukemia, sarcoma, breast cancer, brain
tumor
• Homozygous loss of p53-DNA damage goes
Unrepaired-many mutant genes-cancer
30. APC gene/ ß catenine pathway
• Develop thousands of adenomatous polyps
• APC protein binds and regulates the
degradation of b catenine levels in cytoplasm
• Absence of APC protein-b catenine levels
increase- translocate to nucleus-up regulate
cell proliferation
• APC is a negative regulator of b catenine
34. NF1 gene
• Regulates signal transduction by RAS pathway
• Homozygous loss impairs conversion of active
RAS to inactive RAS
• Germ line inheritance of one mutant allele
predipose to multiple NF
• Loss of 2 nd NF gene - progression to
malignancy
36. WT -1 gene
• WT-1 protein transcriptional activator of
genes involved in renal and gonadal
differentiation
• Tumorigenic function - role in differentiation
of genitourinary tissues
• Wilms’ tumor of kidney
42. HNPCC
Hereditary nonpolyposis colon ca syndrome
• Born with one defective copy of one of several
DNA repair genes involved in mismatch repair
(MSH2 & MLH1)
• Loss of normal spell checker function
• Microsatellite repeats
• Variation in microsatellite – instability
• Hall mark of mismatch repair defects
44. BRCA-1 and BRCA-2
• Involved in repair of double stranded DNA
breaks by homologous recombination
• Familial breast cancers, ovarian ca,
melanoma, pancreatic ca
45. Defects in DNA repair
Self sufficiency in growth signals
Insensitivity to growth inhibitory signals
Evasion of apoptosis
Defects in DNA repair
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasis
47. Limitless replicative potential
teleromerase
• Telomerase not active in somatic cells
• Cellular telomerase progressively shorten with
each cell cycle - replicative senescence
• Cancer cells reactivate telomerase
• 90 % of human tumors show telomerase
activity