pRb undergoes phosphorylation through the cell cycle.
pRb is essentially unphosphorylated when cells are in Go
becomes weakly phosphorlated after entrance into G1
becomes extensively phosphorlated on a much larger number of serine and threonin residues in concert with advance of cells through the R point
pRb usually remains hyperphosphorlated throughout the remainder of the cell cycle.
After cells exit mitosis, the phosphate groups on pRb are stripped off
pRb function is disrupted by onco-proteins
DNA tumor virus encoded onco-protein can disrupt the cellular cycle
E1A oncogene of adenovirus is tightly bound to pRb
E7 onco-protein of human papillomavirus virus (human cervical carcinoma) also binds with pRb in virus-transformed cells
the Rb gene protein product, pRb, must inhibit proliferation in some fashion???
DNA tumor viruses can sequester and apparently inactivating pRb
The same outcome as that occurs after loses the two copies of its chromosomal Rb gene through mutations.
DNA tumor viruses proteins bind preferentially to the hypo-phosphorylated pRb, present in the cell through most in G1 phase
pRb - the guardian of the R-point
pRb is deployed by the cell cycle clock to serve as a guardian of the restriction-point gate until it becomes hyperphosphoylated in which case pRb loses its growth-inhibitory powers, opens the gate
cell to enter into late G1 and thereafter into the remaining phases of the cell cycle.
pRb is the arbiter of growth versus nongrowth
In early and mid-G1, D-type cyclins with their CDK4/6 kinase partners are responsible for initiating pRb phorylation leading to its hypo-phosphorylation.
cyclin E levels increase dramatically at the R point.
The cyclin E then associates with its CDK2 partner, and this complex drives pRb phosphorylation to completion,
pRb becomes hyperphosphorylated, functionally inactive
E2F transcription factors bind to pRb
pRb exercises much of this control through its effects on transcription factors termed E2Fs.
When pRb are unphosphorylated (hypophosphorylated), they bind E2Fs,
when hyperphosphorylated, pRb dissociate from the E2Fs
A simple model of how pRb is able to control cell cycle
In early and middle parts of G1, E2Fs are associated with the promoters of a number of genes under their control.
these transcription factors are bound by pocket proteins (eg. pRb)
This pRb protein association with promoter and prevents the transcription.
During much of the G1 phase of the cell cycle, genes that depend on E2Fs for expression is repressed (by pRb/E2F)
E2F release allows transcription
When the pocket proteins undergo hyper-phosphorylion at the R point in late G1, they release their grip on the E2Fs
permitting the E2F transcription of these genes.
The products of these genes, push the cell from late G1 into S phase.
Similarly, when viral oncoproteins are present, they mimic pRb hyper-phosphorylation by prevent pRb from binding E2Fs
What sort of genes are transcribed?
Genes known or assumed to be important for S-phase entry have promoters for E2Fs.
Genes encoding proteins involved in;
synthesizing DNA,
precursor nucleotides (such as dihydrofolate synthetase and thymidine kinase)
other genes involved directly in DNA replication.
E2F deactivation
As the cell passes G1/S transition into S phase, Cyclin A becomes activated and with its CDK2 partner. This phosphroylates both the E2F and DP subunits of these heterodimeric transcription factors results in the dissociation of the E2F-DP complexes and loss of their transcription-activating abilities.
4 окт 2024
