Selected targets of p53
Selected targets of p53
Tumor protein p53 ( p53 ) is active as a tetramer consisting of four identicalchains of 393 amino acid residues. The N-terminal region contains an intrinsicallydisordered trans-activation domain (TAD) and a proline-rich region. The central, foldedDNA-binding core domain, is responsible for sequence-specific DNA binding. At itsC-terminus, p53 contains the so-called regulatory domain. This natively unfoldedregion is rich in basic amino acids (mainly lysines) and binds DNA nonspecifically [1].
p53 is normally activated by cellular stress and mediates thegrowth-suppressive response that involves cell cycle arrest and apoptosis [2]. In the case of cell cycle arrest, Cyclin-dependent kinase inhibitor 1A (p21 ) appears sufficient to block cell cycle progression out of G1 until DNArepair has occurred, or the cellular stress has been alleviated [3], [2].
The p53 -dependent apoptotic response is complex and involves transcriptionalactivation of multiple pro-apoptotic target genes [2]. There are, forexample, different caspases [4], Cathepsin D [5], Bcl-2family members (B-cell CLL/lymphoma 2 ( Bcl-2 ) and BCL2-associated X protein (Bax )) [6] and BCL2/adenovirus E1B 19kDa interacting protein 3-like (NIX ) [7].
The p53 pathway, either directly or indirectly, is targeted for inactivationin most human cancers. The latter highlights the protein's critical function as a tumorsuppressor gene [2]. This pathway is realized mostly via regulation oftranscription of developmental signaling genes. for example of tumor suppressorsHypermethylated in cancer 1 and 2 ( HIC1/2 ) [8], Brain-specificangiogenesis inhibitor 1 ( BAI1 ) [9], PTK6 protein tyrosine kinase 6( BRK ) [10], Adenomatous polyposis coli ( APC protein ) [11].
In addition, p53 participates in regulation of transport [12],cytoskeletal signaling [13], ECM and adhesion [14], proteintraffic [15] and others processes. Possibly, most of these processes takepart in development of the basic p53 -denendent response (apoptosis, cell cyclearrest, tumor suppression).
Map Key
