From the above, it is evident that although the risk for developing retinoblastoma in retinoblastoma families is inherited as a dominant trait, at the level of the cell, one intact RB gene is all that is needed for normal function.
Although the loss of normal RB genes initially was discovered in retinoblastomas, it is now evident that biallelic loss of this gene is a fairly common feature of several tumors, including breast cancer, small cell cancer of the lung, and bladder cancer. Patients with familial retinoblastoma also are at greatly increased risk for developing osteosarcomas and some soft-tissue sarcomas.
Germ cells Zygote Somatic cells of child Retinal cells Retinoblastoma
Fig. 6.19 Pathogenesisofretinoblastoma.TwomutationsoftheRB chromosomallocus,on13q14,leadtoneoplasticproliferationoftheretinalcells.Inthesporadicform,bothRB mutationsinthetumor-foundingretinalcellareacquired.Inthefamilialform,allsomaticcellsinheritonemutantRB genefromacarrierparent,andasaresultonlyoneadditionalRB mutationinaretinalcellisrequiredforcompletelossofRB function.
http://ebooksmedicine.net
The function of the RB protein is to regulate the G1/S checkpoint, the portal through which cells must pass before DNA replication commences. Although each phase of the cell cycle circuitry is monitored carefully, the transition from G1 to S is an extremely important checkpoint in the cell cycle “clock.” In the G1 phase, diverse signals are integrated to determine whether the cell should progress through the cell cycle, or exit the cell cycle and differentiate. The RB gene product, RB, is a DNA-binding protein that serves as a point of integration for these diverse signals, which ultimately act by altering the phosphorylation state of RB. Specifically, signals that promote cell cycle progression lead to the phosphorylation and inactivation of RB, while those that block cell cycle progression act by maintaining RB in an active hypophosphorylated state.
To appreciate this crucial role of RB in the cell cycle, it is helpful to review the mechanisms that enforce the G1/S transition.
The initiation of DNA replication (S phase) requires the activity of cyclin E/CDK2 complexes, and expression of cyclin E is dependent on the E2F family of transcription factors. Early in G1, RB is in its hypophosphorylated active form, and it binds to and inhibits the E2F family of transcription factors, preventing transcription of cyclin E. Hypophosphorylated RB blocks E2F-mediated transcription in at least two ways (
Fig. 6.20 ). First, it sequesters E2F, preventing it from interacting with other transcriptional activators. Second, RB recruits chromatin remodeling proteins, such as histone deacetylases and histone methyltransferases, which bind to the promoters of E2F-responsive genes such as cyclin E. These enzymes modify chromatin at the promoters to make DNA insensitive to transcription factors.
This situation is changed on mitogenic signaling. Growth factor signaling leads to cyclin D expression and activation of cyclin D–CDK4/6 complexes. The level of cyclin D-CDK4/6 activity is tempered by antagonists such as p16, which is itself subject to regulation by growth inhibitors such as TGFβ that serve to set a threshold for mitogenic responses. If the stimulus is sufficently strong, cyclin D-CDK4/6 complexes phosphorylate RB, inactivating the protein and releasing E2F to induce target genes such as cyclin E. Cyclin E/CDK complexes then stimulate DNA replication and progression through the cell cycle. When the cells enter S phase, they are committed to divide without additional growth factor stimulation. During the ensuing M phase, the phosphate groups are removed from RB by cellular phosphatases, regenerating the hypophosphorylated form of RB.