Fig. 1 The p53 pathway. p53 is activated by different stresses and induces the expression of several genes involved in cell growth inhibition, DNA repair, and apoptosis. p14ARF inactivates MDM2 and stabilizes p53. (View this art in color at www.dekker.com.)

The biochemical activity involves its ability to bind DNA in a sequence-specific manner and to act as a transcription factor. The p53 protein is extensively posttranslationally modified by phosphorylation and acet-ylation, which affect its sequence-specific DNA binding and transcriptional activities. In normally growing cells, p53 protein levels are very low. In response to different cellular stresses, such as DNA damage, oxidative stress, radiations, hypoxia, and so on, p53 is stabilized by covalent and noncovalent modifications, succeeding specific protein-protein interactions that, in turn, rapidly increase p53 protein levels and induce the expression of genes involved in cell cycle arrest to allow repair processes, or, failing that, to induce the expression of genes promoting apoptosis (Fig. 1).[3] Genotoxic damage, also caused by chemotherapy or radiotherapy, induces p53 overexpression to control the rate of proliferating damaged cells, thus triggering the mismatch repair or apoptotic pathway.

The activity of p53 is regulated primarily through control of protein stability. One of the principal regulators of p53 stability is MDM2, which not only binds the transactivation domain of p53, inhibiting its ability to function as a transcription factor, but also targets p53 for degradation. The factor, which can inactivate MDM2 and stabilize p53, is the p14ARF tumor-suppressor gene product that binds directly to MDM2, thereby inhibiting p53 proteolysis (Fig. 1).

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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