TUMOUR SUPRESSOR GENES
It suppresses cell division and growth. It is a loss of function mutation and a recessive one too because both alleles of a TSG needs to be deactivated for tumorigenesis to take place. But, some dominant loss of function mutations are also known.
The two best characterized Tumor Suppressed Genes are:
1)RB 2) p53.
RB locus:
The gene RB is located in band q14 of human chromosome 13. It encodes RB protein .
The loss or inactivation of RB locus is mainly involved in retinoblastoma alongwith other type of cancer such as osteosarcomas and small cell lung cancer.
During the M-to-G1 transition,
pRb is dephosphorylated by PP1, to its growth-suppressive hypophosphorylated state Rb ; so that no growth takes place now.
E2F is actually a group of transcription factor and forms E2F-DP complex with dimerization partner (DP) protein . This dimer activates genes whose products are necessary to push a cell into S phase.
But, When Rb is bound to E2F of E2F-DP complex, the complex acts as a growth suppressor and prevents progression through the cell cycle.
The Rb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors.
When it is time for a cell to enter S phase,
complexes of CDK and cyclins phosphorylate Rb to pRb, inhibiting its activity.The initial phosphorylation is performed by Cyclin D/CDK4/CDK6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phase.
Phosphorylation of Rb allows E2F-DP to dissociate from pRb and become active.When E2F is free it activates factors like cyclins (e.g. Cyclin E and A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or PCNA, which speeds DNA replication and repair by helping to attach polymerase to DNA.
Similarly, p16, p21 and p27 ensure that CDK-4 and 6 remains inactive and thus contribute to tumour supression.
HOW CANCER TAKES PLACE:If both alleles of RB are inactivated; then it leads to absence of RB protein and absence of inhibition of E2F leading to continuous cell division.
Similarly, SV40 T Antigen and E1A protein of adenovirus binds with unphosphorylated RB and deter it from binding to E2F. As a result; E2F remains ever active and contribute to uncontrolled cell division.
p53 gene : p53 is the most important Tumor Suppressor Genes. It is involved in more than half of all cancers.
Initially, p53 was identified as an oncogene but later recognized as a dominant negative mutant.
Wild type p53 controls cell proliferation.
Protein p53 has different domains which help it perform different functions :
It's central domain binds the DNA by recognizing a 10 bp motif in it. SV40 binds to this central domain to deter it from binding DNA.
Now N terminal domian of p53 interacts with TBP to activate transcription of those genes ;whose promoter region contain 10 bp motif to which central domian of p53 has bound.
E1B protein of adenovirus binds with this N terminal domain to block p53 from functioning.
C terminal domain- it works during DNA damage.
If DNA damage is recognized during G1 phase;then p53 binds to the single stranded DNA. Now DNA damage is repaired first and then only cell may enter S phase.
But, if the cell has already committed to division; then p53 triggers apoptosis.
Functional p53 is a tetramer and C terminal domain works to oligomerize it.
It also has a signalling domain which binds to SH3 domain.
p53 as a transcription factor has the following 3 roles:
1) Apoptosis,
2) Cell cycle arrest in G1,
3) Prevention of genomic instability.
CELL CYCLE ARREST IN G1 - Protein p53 binds to single stranded region and to mismatches produced by deletion or addition of 1-3 bases. Thus binding activates the DNA binding and transcription activation domain of p53 and now it leaves the site of damage and activates the target gene.
Transcription of p21 is activated and it prevents the action of CDK4,6-cyclin D and CDK2-cyclin E action, which prevents the onset of S phase.
APOPTOSIS - Protein p53 following it's activation by damaged DNA activates genes leading to apoptosis.
PREVENTION OF GENOMIC INSTABILITY - Level of p53 is regulated by interaction between p53 and cellular oncoprotein Mdm2. An increase in p53 level induces transcription of Mdm2. Increase in Mdm2 level now inhibits p53 activity. This interaction maintains a low level of both proteins in normal cells.
Transcription activation by p53 requires the coactivators p300/CBP; . p300 binds the transcription activation domain of p53; thus helps Mdm2 to bind to p53. Binding of Mdm2 to p53 makes it an easy tsrget for degradation and thus helps to inhibit transcription activation by p53.
Protein p53 is modified in response to environmental signals thst influence cell growth. Signals like ionizing and UV irradiation cause acetylation of lysine, phosphorylation and dephosphorylation of serine at specific position of p53. These changes maty affect the stability, DNA binding ,oligomerization,, and binding to other proteins. Thus, p53 acts as a sensor that integrates information from many pathways that affect cell division.
NOTE- Both p53 and RB are activated by multiple pathways. Locus INK4A-ARF affects the function of both RB and p53. This locus produces p16 and p29. p16 prevents both assembly and activity of CDK-4,6-cyclin D ; as a result, RB remains active.
Similarly, p19 inactivates Mdm2 and this retains p53 active.
It suppresses cell division and growth. It is a loss of function mutation and a recessive one too because both alleles of a TSG needs to be deactivated for tumorigenesis to take place. But, some dominant loss of function mutations are also known.
The two best characterized Tumor Suppressed Genes are:
1)RB 2) p53.
RB locus:
The gene RB is located in band q14 of human chromosome 13. It encodes RB protein .
The loss or inactivation of RB locus is mainly involved in retinoblastoma alongwith other type of cancer such as osteosarcomas and small cell lung cancer.
During the M-to-G1 transition,
pRb is dephosphorylated by PP1, to its growth-suppressive hypophosphorylated state Rb ; so that no growth takes place now.
E2F is actually a group of transcription factor and forms E2F-DP complex with dimerization partner (DP) protein . This dimer activates genes whose products are necessary to push a cell into S phase.
But, When Rb is bound to E2F of E2F-DP complex, the complex acts as a growth suppressor and prevents progression through the cell cycle.
The Rb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors.
When it is time for a cell to enter S phase,
complexes of CDK and cyclins phosphorylate Rb to pRb, inhibiting its activity.The initial phosphorylation is performed by Cyclin D/CDK4/CDK6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phase.
Phosphorylation of Rb allows E2F-DP to dissociate from pRb and become active.When E2F is free it activates factors like cyclins (e.g. Cyclin E and A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or PCNA, which speeds DNA replication and repair by helping to attach polymerase to DNA.
Similarly, p16, p21 and p27 ensure that CDK-4 and 6 remains inactive and thus contribute to tumour supression.
HOW CANCER TAKES PLACE:If both alleles of RB are inactivated; then it leads to absence of RB protein and absence of inhibition of E2F leading to continuous cell division.
Similarly, SV40 T Antigen and E1A protein of adenovirus binds with unphosphorylated RB and deter it from binding to E2F. As a result; E2F remains ever active and contribute to uncontrolled cell division.
p53 gene : p53 is the most important Tumor Suppressor Genes. It is involved in more than half of all cancers.
Initially, p53 was identified as an oncogene but later recognized as a dominant negative mutant.
Wild type p53 controls cell proliferation.
Protein p53 has different domains which help it perform different functions :
It's central domain binds the DNA by recognizing a 10 bp motif in it. SV40 binds to this central domain to deter it from binding DNA.
Now N terminal domian of p53 interacts with TBP to activate transcription of those genes ;whose promoter region contain 10 bp motif to which central domian of p53 has bound.
E1B protein of adenovirus binds with this N terminal domain to block p53 from functioning.
C terminal domain- it works during DNA damage.
If DNA damage is recognized during G1 phase;then p53 binds to the single stranded DNA. Now DNA damage is repaired first and then only cell may enter S phase.
But, if the cell has already committed to division; then p53 triggers apoptosis.
Functional p53 is a tetramer and C terminal domain works to oligomerize it.
It also has a signalling domain which binds to SH3 domain.
p53 as a transcription factor has the following 3 roles:
1) Apoptosis,
2) Cell cycle arrest in G1,
3) Prevention of genomic instability.
CELL CYCLE ARREST IN G1 - Protein p53 binds to single stranded region and to mismatches produced by deletion or addition of 1-3 bases. Thus binding activates the DNA binding and transcription activation domain of p53 and now it leaves the site of damage and activates the target gene.
Transcription of p21 is activated and it prevents the action of CDK4,6-cyclin D and CDK2-cyclin E action, which prevents the onset of S phase.
APOPTOSIS - Protein p53 following it's activation by damaged DNA activates genes leading to apoptosis.
PREVENTION OF GENOMIC INSTABILITY - Level of p53 is regulated by interaction between p53 and cellular oncoprotein Mdm2. An increase in p53 level induces transcription of Mdm2. Increase in Mdm2 level now inhibits p53 activity. This interaction maintains a low level of both proteins in normal cells.
Transcription activation by p53 requires the coactivators p300/CBP; . p300 binds the transcription activation domain of p53; thus helps Mdm2 to bind to p53. Binding of Mdm2 to p53 makes it an easy tsrget for degradation and thus helps to inhibit transcription activation by p53.
Protein p53 is modified in response to environmental signals thst influence cell growth. Signals like ionizing and UV irradiation cause acetylation of lysine, phosphorylation and dephosphorylation of serine at specific position of p53. These changes maty affect the stability, DNA binding ,oligomerization,, and binding to other proteins. Thus, p53 acts as a sensor that integrates information from many pathways that affect cell division.
NOTE- Both p53 and RB are activated by multiple pathways. Locus INK4A-ARF affects the function of both RB and p53. This locus produces p16 and p29. p16 prevents both assembly and activity of CDK-4,6-cyclin D ; as a result, RB remains active.
Similarly, p19 inactivates Mdm2 and this retains p53 active.
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