The retinoblastoma protein is a tumor suppressor protein that is dysfunctional
in several major cancers. One function of pRb is to prevent excessive cell
growth by inhibiting cell cycle progression until a cell is ready to
divide. When the cell is ready to divide, pRb is phosphorylated, becomes
inactive and allows cell cycle progression. It is also a recruiter of
several chromatin remodeling enzymes such as methylases and acetylases.
Rb belongs to the pocket protein family, whose members have a pocket for the
functional binding of other proteins. Should an oncogenic protein, such as
those produced by cells infected by high-risk types of human
papillomaviruses, bind and inactivate pRb, this can lead to cancer.
Name and genetics In humans, the protein is encoded by the
RB1 gene located on 13q14.1-q14.2. If both alleles of this gene are mutated
early in life, the protein is inactivated and results in development
of retinoblastoma cancer, hence the name Rb. Retinal cells are not sloughed off
or replaced, and are subjected to high levels of mutagenic UV radiation, and
thus most pRB knock-outs occur in retinal tissue.
Two forms of retinoblastoma were noticed: a bilateral, familial form and
a unilateral, sporadic form. Sufferers of the former were 6 times more likely
to develop other types of cancer later in life. This highlighted the fact that
mutated Rb could be inherited and lent support to the two-hit hypothesis. This
states that only one working allele of a tumour suppressor gene is necessary for
its function, and so both need to be mutated before the cancer phenotype will
appear. In the familial form, a mutated allele is inherited along with a normal
allele. In this case, should a cell sustain only one mutation in the other
RB gene, all Rb in that cell would be ineffective at inhibiting cell cycle
progression, allowing cells to divide uncontrollably and eventually become
cancerous. Furthermore, as one allele is already mutated in all other somatic
cells, the future incidence of cancers in these individuals is observed with
linear kinetics. The working allele need not undergo a mutation per se, as loss
of heterozygosity is frequently observed in such tumours.
However, in the sporadic form, both alleles would need to sustain a mutation
before the cell can become cancerous. This explains why sufferers of sporadic
retinoblastoma are not at increased risk of cancers later in life, as both
alleles are functional in all their other cells. Future cancer incidence in
sporadic Rb cases is observed with polynomial kinetics, not exactly
quadratic as expected because the first mutation must arise through normal
mechanisms, and then can be duplicated by LOH to result in a tumour progenitor.
RB1 orthologs have also been identified in most mammals for which complete
genome data are available. RB/E2F-family proteins repression
transcription. Cell cycle suppression
Rb restricts the cell's ability to replicate DNA by preventing its
progression from the G1 to S phase of the cell division cycle. Rb binds and
inhibits transcription factors of the E2F family, which are composed of dimers
of an E2F protein and a dimerization partner protein. The transcription
activating complexes of E2 promoter-binding–protein-dimerization
partners can push a cell into S phase. As long as E2F-DP is inactivated, the
cell remains stalled in the G1 phase. When Rb is bound to E2F, the complex
acts as a growth suppressor and prevents progression through the cell cycle. The
Rb-E2F/DP complex also attracts a histone deacetylase protein to the
chromatin, reducing transcription of S phase promoting factors, further
suppressing DNA synthesis. Detection
Several methods for detecting the RB1 gene mutations have been developed
including a method that can detect large deletions that correlate with advanced
stage retinoblastoma. Activation and inactivation
Rb is phosphorylated to pRb by certain cyclin-dependent kinases. pRb is
described as being hyperphosphorylated and when in this state, it is unable to
complex E2F and therefore, unable to restrict progression from the G1 phase
to the S phase of the cell cycle. During the M-to-G1 transition, pRb is
progressively dephosphorylated by PP1, returning to its growth-suppressive
hypophosphorylated state Rb . When it is time for a cell to enter S
phase, complexes of cyclin-dependent kinases and cyclins phosphorylate Rb to
pRb, inhibiting its activity. The initial phosphorylation is performed by
Cyclin DCDK6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb
remains phosphorylated throughout S, G2 and M phases.
Phosphorylation of Rb allows E2F-DP to dissociate from pRb and become active.
When E2F is free it activates factors like cyclins, 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.
Rb family proteins are components of the DREAM complex, which is composed of
LIN9, LIN54, LIN37, MYBL2, RBL1, RBL2, RBBP4, TFDP1, TFDP2, E2F4 and E2F5.
There is a testis-specific version of the complex, where LIN54, MYBL2 and
RBBP4 are replaced by MTL5, MYBL1 and RBBP7, respectively. In Drosophila both
DREAM versions also exist, the components being mip130, mip120, and
Myb, Caf1p55, DP, Mip40, E2F2, Rbf and Rbf2. The DREAM complex exists in
quiescent cells in association with MuvB where it represses cell cycle-dependent
genes. DREAM dissociates in S phase from MuvB and gets recruited by MYB.
Regeneration = Cochlea =
The retinoblastoma protein is involved in the growth and development of
mammalian hair cells of the cochlea, and appears to be related to the cells'
inability to regenerate. Embryonic hair cells require Rb, among other important
proteins, to exit the cell-cycle and stop dividing, which allows maturation
of the auditory system. Once wild-type mammals have reached adulthood, their
cochlear hair cells become incapable of proliferation. In studies where the gene
for Rb is deleted in mice cochlea, hair cells continue to proliferate in early
adulthood. Though this may seem to be a positive development, Rb-knockdown mice
tend to develop severe hearing loss due to degeneration of the organ of Corti.
For this reason, Rb seems to be instrumental for completing the
development of mammalian hair cells and keeping them alive. However, it is clear
that without Rb, hair cells have the ability to proliferate, which is why Rb
is known as a tumor suppressor. Temporarily and precisely turning off Rb
in adult mammals with damaged hair cells may lead to propagation and therefore
successful regeneration. Suppressing function of the retinoblastoma protein
in the adult rat cochlea has been found to cause proliferation of supporting
cells and hair cells. Rb can be downregulated by activating the sonic
hedgehog pathway, which phosphorylates the proteins and reduces gene
transcription. = Neurons =
Disrupting Rb expression in vitro, either by gene deletion or knockdown of
Rb short interfering RNA, causes dendrites to branch out farther. In
addition, Schwann cells, which provide essential support for the survival of
neurons, travel with the neurites, extending farther than normal. The
inhibition of Rb supports the continued growth of nerve cells.
Interactions Retinoblastoma protein has been shown to
interact with: See also
p53 - involved in the DNA repair support function of pRb
Transcription coregulator Retinoblastoma
References Further reading
External links RB1 protein, human at the US National
Library of Medicine Medical Subject Headings
Retinoblastoma genes at the US National Library of Medicine Medical Subject
Headings GeneReviewsNCBI/UW entry on
Retinoblastoma Retinoblastoma Genetics
Drosophila Retinoblastoma-family protein - The Interactive Fly
Drosophila Retinoblastoma-family protein 2 - The Interactive Fly
Evolutionary Homologs Retinoblastoma-family proteins - The
Interactive Fly There is a diagram of the pRb-E2F
interactions here. This article incorporates text from the
United States National Library of Medicine, which is in the public domain.