The Retinoblastoma Gene and Protein

The RB1 gene consists of 27 exons and occupies over 183 kb of genomic sequence on chromosome 13q14. A CpG-island, which is normally unmethylated, is located at its 5'-end. In diverse tissues, the gene is transcribed into a 4.7-kb mRNA, which contains a 2.7-kb open reading frame. Orthologs with a high level of sequence similarity in translated regions of the human RB1 gene have been identified in several vertebrate organisms.

The protein encoded by the RB1 gene, pRb, is a 928-amino acid nuclear phosphoprotein that migrates at 110 kDa in SDS-PAGE when hypophosphorylated. It belongs to a small family of nuclear proteins that includes p107 and p130. These proteins are termed pocket proteins because of significant sequence similarity in two discontinuous regions (pockets A and B). Conditional on the phosphorylation status at multiple serine and threonine residues, this pocket can bind to members of the E2F family of transcription factors as well as to endogenous nuclear proteins that contain the LxCxE peptide motif. The C-terminal region of pRB contains a nuclear localization signal and a cyclin-cdk interaction motif that enables it to be recognized and phosphorylated by cyclin-cdk complexes. In addition, C-terminal region can bind to the nuclear c-Abl tyrosine kinase and to MDM2. One role of pRb is its function as a gatekeeper that negatively regulates progression through the G1 phase of the cell cycle. During the G1 phase of the cell cycle pRb is hypophosphorylated. This form can bind E2F and causes a repression of E2F-mediated transcription. Beginning in late G1 and continuing to the M phase, pRB is phos-phorylated by G1 cyclin-dependent kinases. Upon phos-phorylation of pRb, E2F is released and promotes transcription of genes that are required for cell division. Consequently, pRB controls cell-cycle phase transition by transcriptional repression. In addition to phosphorylation, cell cycle-dependent acetylation has been found to control pRb function. Acetylation hinders phosphorylation of pRb and enhances binding to the MDM2 oncoprotein. However, besides cell-cycle regulation, pRb has several other roles including control of apoptosis and stimulation of differentiation (for review of pRB functions, see Refs. [11-13]).

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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