Retinoblastoma and E2F Protein
- Retinoblastoma is a human childhood disease, involving a tumor of the retina.
- It occurs both as a heritable trait and sporadically (by somatic mutation).
- It is often associated with deletions of band q 14 of human chromosome 13.
- The RB gene has been localized to this region by molecular cloning.
Summarizes the situation.
- Retinoblastoma arises when both copies of the RB gene are in-parental chromosome carries an alteration in this region.
- A somatic event in retinal cells that causes loss of the other copy of the RB gene causes a tumor.
- In the sporadic form of the disease, the parental chromosomes are normal, and both RB alleles are lost by (individual) somatic events.
- The cause of retinoblastoma is therefore loss of protein function.
- Loss of RB is involved also in other forms of cancer, including osteosarcomas and small cell lung cancers.
- RB is a nuclear phosphoprotein that influences the cell cycle.
- In resting (G0/G1) cells, RB is not phosphorylated.
- RB is phoshorylated during the cell cycle by cyclin/cdk complexes, most particularly at the end of G1; it is dephosphorylated during mitosis.
- The non-phosphorylated form of RB specifically binds several protein, and these interactions therefore occur only during part of the cell cycle (prior to S phase).
- Phosphorylation releases these protein.
- The target proteins include the E2F group of transcription factors, which activate target genes whose products are essential for S phase.
- Binding to RB inhibits the ability of E2F to activate transcription,
- Which suggests that RB may repress the expression of genes dependent on E2F.
- In this way, RB indirectly prevents cells from entering S phase.
- Also, the RB-E2F complex directly represses some target genes, so its dissociation allows them to be expressed.
- Certain viral tumor antigens bind specifically to the non-phosphorylated from of RB.
- The best characterized are SV40 T antigen and adenovirus E1A.
- This suggests the model shown in Non-phosphorylated RB prevents cell proliferation , this activity must be suppressed in order to pass through the cell cycle, which is accomplished by the cyclic-phosphorylation.
- And it may also be suppressed when a tumor antigen sequesters the non-phosphorylated bind E2F, the E2F is permanently free to allow entry into S phase (and the RB-E2F complex is not available to repress its target genes.)
Over-expression of RB impedes cell growth.
- An indication of the importance of RB for cell proliferation is given by the properties of an osteosarcoma cell line that lacks RB;
- when RB is introduced into this cell line, its growth is impeded.
- However, the inhibition can be overcome by expression of D cyclins, which form cdk-cyclin combinations that phosphorylate RB. RB is not the only proteins of its type : proteins with related sequences, called p107 and p130, have similar properties.
- The connection between the cell cycle and tumor genesis is illustrated in several regulators are identified as tumor suppressors by the occurrence of inactivating mutations in tumors.
- In addition to RB itself, there are the small inhibitory proteins (most notably p16 and possibly p21), and D cyclin.
- Although these proteins (most notable RB) play a role in the cycle of a proliferating cell, the role that is relevant for tumor-genesis is more probably their function in the quiescent (G0) state.
- In quiescent cells, RB is not phosphorylated,
- D cyclin levels are low or absent, and p16, p21 p27 ensure inactivity of cdk-cyclin complexes,
- The loss of this circuit is necessary for unrestrained growth.
- Retinoblastoma is a type of tumor affecting which part of the human body?
A) Liver
B) Retina
C) Skin
D) Bone
Answer: B) Retina - Retinoblastoma can occur as a:
A) Heritable disease only
B) Sporadic mutation only
C) Both heritable and sporadic forms
D) Only in adults
Answer: C) Both heritable and sporadic forms - Which human chromosome band is often deleted in retinoblastoma?
A) 21q11
B) 13q14
C) 7p22
D) 1q21
Answer: B) 13q14 - The gene involved in retinoblastoma is known as:
A) TP53
B) E2F
C) RB
D) ATM
Answer: C) RB - What causes retinoblastoma in heritable cases?
A) Viral infection
B) Both alleles of RB gene are mutated (one inherited, one somatic)
C) Only somatic mutations
D) Only germline mutations
Answer: B) Both alleles of RB gene are mutated (one inherited, one somatic) - What type of mutation causes sporadic retinoblastoma?
A) Germline only
B) Only one allele mutation
C) Somatic mutations affecting both alleles
D) Chromosome translocation
Answer: C) Somatic mutations affecting both alleles - Loss of RB protein function can lead to:
A) Anemia
B) Cancer
C) Apoptosis only
D) Diabetes
Answer: B) Cancer - RB gene mutations are also found in which other cancers?
A) Osteosarcoma
B) Small cell lung carcinoma
C) Both A and B
D) Melanoma
Answer: C) Both A and B
- RB is a type of:
A) Cytoplasmic protein
B) Nuclear phosphoprotein
C) Membrane receptor
D) Ribosomal protein
Answer: B) Nuclear phosphoprotein - In which cell cycle phase is RB dephosphorylated?
A) G1
B) S
C) Mitosis
D) G2
Answer: C) Mitosis - When is RB phosphorylated during the cell cycle?
A) G0 phase
B) Early G1
C) End of G1 phase
D) S phase
Answer: C) End of G1 phase - Unphosphorylated RB binds to which transcription factor?
A) p53
B) Myc
C) E2F
D) ATM
Answer: C) E2F - What is the function of RB binding to E2F?
A) Activates E2F
B) Degrades E2F
C) Inhibits E2F-mediated transcription
D) Transports E2F to cytoplasm
Answer: C) Inhibits E2F-mediated transcription - What happens when RB is phosphorylated?
A) It binds to E2F
B) It is degraded
C) It releases E2F
D) It activates CDK4
Answer: C) It releases E2F - Free E2F activates genes required for which phase?
A) G2
B) S
C) M
D) G0
Answer: B) S - RB-E2F complex also functions as:
A) Gene activator
B) DNA repair enzyme
C) Transcriptional repressor
D) Oncogene
Answer: C) Transcriptional repressor
- What happens when E2F is permanently free?
A) Cell cycle arrest
B) Entry into S phase
C) Apoptosis
D) DNA repair
Answer: B) Entry into S phase - Which viral proteins can bind to unphosphorylated RB?
A) p53
B) E1A and SV40 T antigen
C) Caspase 3
D) CDK2
Answer: B) E1A and SV40 T antigen - What is the role of viral antigens binding to RB?
A) Promote apoptosis
B) Suppress DNA synthesis
C) Sequester RB and promote cell proliferation
D) Activate RB
Answer: C) Sequester RB and promote cell proliferation - Overexpression of RB results in:
A) Enhanced cell division
B) Cell growth inhibition
C) Cell apoptosis
D) Oncogenesis
Answer: B) Cell growth inhibition - Reintroducing RB into RB-null osteosarcoma cells causes:
A) Rapid growth
B) Cell shrinkage
C) Cell cycle arrest or inhibition
D) Chromosome fusion
Answer: C) Cell cycle arrest or inhibition - Which cyclins can overcome RB-mediated inhibition?
A) Cyclin A
B) Cyclin B
C) D-type cyclins
D) Cyclin E
Answer: C) D-type cyclins
- RB-related proteins with similar sequences include:
A) p21 and p53
B) ATM and ATR
C) p107 and p130
D) E2F and DP1
Answer: C) p107 and p130 - Loss of RB function is most significant in which state of the cell?
A) Dividing cell
B) Apoptotic cell
C) Quiescent (G0) state
D) M phase
Answer: C) Quiescent (G0) state - What ensures inactivity of CDK-cyclin complexes in G0?
A) Cyclin D overexpression
B) High p16, p21, p27 levels
C) High CDK levels
D) RB phosphorylation
Answer: B) High p16, p21, p27 levels - Which of the following are small inhibitory tumor suppressor proteins?
A) p21
B) p16
C) p27
D) All of the above
Answer: D) All of the above - Which of the following is NOT involved in suppressing CDK activity in G0?
A) p16
B) p53
C) p21
D) p27
Answer: B) p53 - When D-type cyclins are low or absent, the cell is likely in:
A) G1 phase
B) G2 phase
C) Mitosis
D) G0 phase
Answer: D) G0 phase
- Phosphorylation of RB by D-cyclin-CDK complexes promotes:
A) Cell apoptosis
B) Entry into mitosis
C) Transition from G1 to S phase
D) Exit from the cell cycle
Answer: C) Transition from G1 to S phase - RB inhibits cell proliferation primarily by:
A) Binding and degrading DNA
B) Enhancing translation
C) Inhibiting transcription of S-phase genes
D) Preventing mitosis
Answer: C) Inhibiting transcription of S-phase genes - Which statement is true about RB function in cancer?
A) It is always active
B) It is phosphorylated in G0
C) Its inactivation leads to uncontrolled growth
D) It binds to ATP for energy
Answer: C) Its inactivation leads to uncontrolled growth - The RB gene product acts as a:
A) Proto-oncogene
B) Tumor suppressor
C) Growth factor
D) Kinase
Answer: B) Tumor suppressor - Which of these events can mimic RB loss?
A) E2F degradation
B) D-cyclin overexpression
C) Decrease in CDKs
D) DNA methylation
Answer: B) D-cyclin overexpression - What does the RB-E2F complex directly repress?
A) Mitosis-specific genes only
B) DNA repair genes
C) E2F target genes
D) Cytoplasmic proteins
Answer: C) E2F target genes
- (PYQ: CSIR-NET 2017)
Loss of function of RB protein leads to:
A) Enhanced DNA repair
B) Apoptosis
C) Unregulated progression into S phase
D) Increased protein synthesis
Answer: C) Unregulated progression into S phase
- (PYQ: GATE 2018)
Which statement about E2F is correct?
A) E2F degrades RB protein
B) E2F transcription is active in G0 phase
C) E2F activates genes needed for S phase
D) E2F promotes apoptosis
Answer: C) E2F activates genes needed for S phase
- (PYQ: DBT-JRF 2020)
Which complex directly represses S-phase genes until phosphorylated?
A) Cyclin D-CDK4
B) RB-E2F
C) Cyclin B-CDK1
D) APC-Cdc20
Answer: B) RB-E2F
- (PYQ: ICAR JRF 2021)
Which viral antigen is known to bind unphosphorylated RB?
A) HPV E6
B) SV40 T antigen
C) Caspase-9
D) BRCA1
Answer: B) SV40 T antigen
- (PYQ: CSIR-NET 2016)
Introduction of wild-type RB gene into RB-null cells causes:
A) Enhanced proliferation
B) Transformation
C) Inhibition of cell growth
D) Increased mutation rate
Answer: C) Inhibition of cell growth
- (PYQ: GATE 2019)
Which protein is phosphorylated at the end of G1 to allow entry into S phase?
A) CDK1
B) RB
C) E2F
D) APC
Answer: B) RB
- (PYQ: CSIR-NET 2015)
Which of the following represses transcription of E2F target genes in G1?
A) Cyclin A-CDK2
B) CDK4
C) RB protein
D) Cyclin B-CDK1
Answer: C) RB protein
- (PYQ: GATE XL Life Sciences 2020)
Loss of RB function results in:
A) Arrest in G2
B) Decrease in cyclin D
C) Premature entry into S phase
D) Activation of caspase
Answer: C) Premature entry into S phase
- (PYQ: CSIR-NET 2014)
What occurs when RB is bound to E2F?
A) S-phase genes are repressed
B) RB is degraded
C) DNA replication is activated
D) CDK2 is activated
Answer: A) S-phase genes are repressed
- (PYQ: DBT-JRF 2023)
Which of the following can mimic the effect of RB loss in the cell cycle?
A) Overexpression of p21
B) Downregulation of CDKs
C) Overexpression of D cyclins
D) Suppression of E2F
Answer: C) Overexpression of D cyclins
- (PYQ: ICAR NET 2022)
In quiescent cells, RB is generally:
A) Hyperphosphorylated
B) Ubiquitinated
C) Non-phosphorylated
D) Activated by E2F
Answer: C) Non-phosphorylated
- (PYQ: CSIR-NET 2018)
In which condition is the RB protein found in its unphosphorylated state?
A) G2 Phase
B) M Phase
C) S Phase
D) G0/G1 Phase
Answer: D) G0/G1 Phase
- (PYQ: GATE 2021)
What ensures E2F is free to promote S-phase entry?
A) Cyclin A
B) Phosphorylation of RB
C) Degradation of RB
D) Activation of p21
Answer: B) Phosphorylation of RB
- (PYQ: DBT 2016)
Which of the following is not an RB family member?
A) p130
B) p107
C) p27
D) RB
Answer: C) p27
- (PYQ: CSIR-NET 2019)
What is the role of p16 in the RB-E2F pathway?
A) Activates E2F
B) Promotes RB degradation
C) Inhibits CDK4
D) Phosphorylates RB
Answer: C) Inhibits CDK4
- (PYQ: ICAR PG 2020)
Why does tumor antigen binding to RB promote cancer?
A) It degrades DNA
B) It prevents apoptosis
C) It keeps E2F permanently active
D) It inhibits CDK1
Answer: C) It keeps E2F permanently active