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Figure 3.3.13.A. The P53 family. (a) The p53 family includes threegenes that encode P53, P63, and P73. The overall domain structure of P53, P63, and P73 is conserved. In contrast to P53, P63, and P73 have many different isoforms with distinct NH2- and COOH-termini. Full length-isoforms contain the transactivation domain, and are designated TA. NH2-terminally deleted isoforms are designated N. Dashed lines indicate different isoforms. (b) The functions of the TA and N isoforms are summarized. (c) Structure of the P53 DNA-binding domain. Even though the DNA-binding domains of P73 and P53 display only 63% identity in amino acid sequence, the three-dimensional structure of the region of interaction with DNA is almost identical (left), indicating recognition of the same transcriptional targets. Most of the differences are located on the outside surface (right), indicating differential protein-protein interactions and regulation. Residues that are identical in P53 and P73 are shown in red, amino acids that are changed in P73 are in white. DNA is shown in yellow. DBD = DNA-binding domain, OD = oligomeriza-tion domain, PR = proline-rich domain, SAM = sterile a motif. [Reproduced from Melino et al. 2002. With permission from Macmillan.]

Figure 3.3.13.A. The P53 family. (a) The p53 family includes threegenes that encode P53, P63, and P73. The overall domain structure of P53, P63, and P73 is conserved. In contrast to P53, P63, and P73 have many different isoforms with distinct NH2- and COOH-termini. Full length-isoforms contain the transactivation domain, and are designated TA. NH2-terminally deleted isoforms are designated N. Dashed lines indicate different isoforms. (b) The functions of the TA and N isoforms are summarized. (c) Structure of the P53 DNA-binding domain. Even though the DNA-binding domains of P73 and P53 display only 63% identity in amino acid sequence, the three-dimensional structure of the region of interaction with DNA is almost identical (left), indicating recognition of the same transcriptional targets. Most of the differences are located on the outside surface (right), indicating differential protein-protein interactions and regulation. Residues that are identical in P53 and P73 are shown in red, amino acids that are changed in P73 are in white. DNA is shown in yellow. DBD = DNA-binding domain, OD = oligomeriza-tion domain, PR = proline-rich domain, SAM = sterile a motif. [Reproduced from Melino et al. 2002. With permission from Macmillan.]

102 to 292, contains four conserved regions (II-V) and forms a zinc finger structure with four-stranded and five-stranded antiparallel P-sheets. Most frequently, tumor-associated mutations occur in this area.

- A central region (residues 300-360) includes a flexible linker region (amino acids 300-318), connecting the central core domain and a tetramerization domain from amino acids 323-356. A nuclear localization signal (NLS) is present in this moiety of P53. Mutations in NLS1 (amino acids 316-325) retain P53 in the cytoplasm. Also in this region, there is a nuclear export signal between amino acids 320 and 355. The nuclear export signal of P53 is masked by tetramer formation, but functional, when P53 is either a monomer or a dimer.

- COOH-terminal to the oligomerization domain, there is a basic region (amino acids 363-393), which is also known as an apoptopic domain, a transcrip-tional regulatory domain, or a DNA damage recognition domain. This extreme COOH-terminal domain acts as a negative regulator of P53 sequence-specific binding. Two nuclear localization signals are present in the COOH-terminal region. Mutations of NLS2 (amino acids 369-375) or NLS3 (amino acids 379-384) lead to partially cyto-plasmic and partially nuclear localization.

The transcriptional activity for specific genes exerted by P53 is most relevant to its tumor suppressing function (Table 3.3.13.A). Specificity in the transcriptional activity of P53 is achieved by its association with diverse coactivators.

- P53 activation leads to cell cycle arrest. The most important protein relative to cell cycle control, whose transcription is induced by P53, is the Cyclin-Dependent Kinase inhibitor P21, which binds to and inhibits G1 CDK/Cyclin complexes. As a result, cells with damaged DNA are arrested in Gj until the damage is repaired and the levels of P53 and P21 fall. The cells then can progress to S phase. This depends, in part, on coactivators, including P300/CBP, TAFII31, or AD A3. Interactions with c-ABL stabilize the tetrameric conformation of P53 and, as a consequence, stimulate P53 DNA binding to four-quarter binding sites (perfect binding sequences). Such sequences are present in the promoter for p21, but not in the promoter for bax. c-ABL selectively activates P53-mediated growth arrest [Wei et al. 2005].

- Alternatively, accumulation of P53 also leads to the expression of proteins that promote apoptosis. The

Table 3.3.13. A. Gene products, the expression of which is induced by P53. P53 regulates cell apoptosis and cycle progression. It also activates autoregulatory mechanisms that assure the temporal limitation of P53 activity

Death receptors

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