pRB protein
Pocket protein family 13q14.1-q14.2
Chromatin condensation starting in “Prophase” as
well as proper attachment to the spindle.
Failure of pRB function during mitosis leads to
“aneuploidy” and
“Chromosome breakage”
inhibits cell cycle
Recruits several “Chromatin remodeling “ enzymes such as methylases and acetylases
The first tumor supressor gene cloned (1986)
Retinoblastoma
Unilateral
Bilateral – familial form A mutated/deleted & a
normal allele
Both are normal, mutations somatic, only at eye; other cells are normal
• Unilateral- Sporadic- a single tumor appears in
one eye some time in early child hood before the retina fully developed
• Bilateral- familial form- multiple tumors in the 1
stweek of infancy (Germ line mutations + Somatic
mutations)
• pRb binds & inhibits
transcription factors of the E2F family, composed of dimers of an E2F protein & a DP protein
• Transcription activating complexes of E2 promoter binding protein dimerization partners (E2F-DP) can push a cell into “S” phase.
• As long as E2F-DP is
inactivated
, the cell remaining in the G1 phase.• When pRb bound to E2F- it act as growth supressor &
prevents progression through cell cycle
Cell cycle repression G1- S phase
The pRb-E2F/DP attracts histone deacetylase(HDAC) to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis
Activation and inactivation
Hypophopshorylate Tumor
suppressor
Active
Inactive
Phop shory lated
pRb
Initial phosphorylations-by cyclin D/CDK4/CDK6
Additional phosphorylations-by cyclin E/CDK2
Dephosphorylated by Phosphoprotein phsophotase-I
Once phosphorylated, pRB disassociates from the transcription factor E2F1, liberating E2F1 from its cytoplasm bound state allowing it to enter the nucleus.
Once in the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase
pRb -multifunctional protein, with many binding and phosphorylation sites
it binds and inhibits E2promoter- binding-protein-dimerization partner (E2F-DP) which are transcription factors of the E2F family
• pRb-E2F-DP- It activates factors like cyclins (cyclin E & A)
• Which push the cell through the cell cycle by activating cyclin
dependent kinases & Proliferating cell nuclear antigen or PCNA
• Speeds DNA replication and
repair by helping to attach
polymerase to DNA
Rb- Multiple binding pockets
N C
A B
E2F
HDAC 1,2,3;
D- cyclins
~100 pRb binding proteins reported
CDK binding
PENEF.Q
PAIAbl BRCA1 AT hook
