Signaling to p53: breaking the posttranslational modification code.

摘要: In unstressed cells, the tumor suppressor protein p53, a tetrameric transcription factor, is present in latent state and maintained at low levels through targeted degradation. A variety of cellular stresses including DNA damage, hypoxia, nucleotide depletion, viral infection, cytokine-activated signaling pathways that transiently stabilize p53 protein, cause it to accumulate nucleus, activate as factor. Activation leads either growth arrest G1/S or G2/M transitions cell cycle apoptosis. The molecular mechanisms by which stabilization activation occur are incompletely understood, but accumulating evidence points roles for multiple posttranslational modifications mediating these events several potentially interacting distinct pathways. Both approximately 100 amino acid N-terminal 90 C-terminal domains highly modified phosphorylation acetylation, whereas central sequence-specific binding domain have not been reported. Seven serines one threonine first 46 residues transactivation four five carboxyl-terminal now known be phosphorylated, Lys320 Lys382 (human p53) can acetylated. Antibodies recognize only when has specific sites developed laboratories, studies with shown most induced cells exposed DNA-damaging agents. Exceptions Ser378, reported constitutively Ser376, dephosphorylated response damage. These recent results, coupled biochemical genetic studies, suggest amino-terminal phosphorylations important stabilizing damage directing acetylation sites. damage-induced C-terminus inhibit ability this negatively regulate inducing conformational change inhibiting non-sequence-specific C-terminus. also modulate oligomerization may nuclear import/export. Modifications other components interact important. cases, clear modifications, interactions among individual enzymes responsible each modification remain defined. Nevertheless, field appears poised major advances understanding function.