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Abstract: Tumor suppressor p53 is the most frequently mutated gene in human tumors. Meanwhile, under stress conditions, p53 also acts as a transcription factor, regulating the expression of a series of target genes to maintain the integrity of genome. The target genes of p53 can be classified into genes regulating cell cycle arrest, genes involved in apoptosis, and genes inhibiting angiogenesis. p53 protein contains a transactivation domain, a sequence-specific DNA binding domain, a tetramerization domain, a non-specific DNA binding domain that recognizes damaged DNA, and a later identified proline-rich domain. Under stress, p53 proteins accumulate and are activated through two mechanisms. One, involving ataxia telangiectasia-mutated protein (ATM), is that the interaction between p53 and its down-regulation factor murine double minute 2 (MDM2) decreases, leading to p53 phosphorylation on Ser15, as determined by the post-translational mechanism; the other holds that p53 increases and is activated through the binding of ribosomal protein L26 (RPL26) or nucleolin to p53 mRNA 5( untranslated region (UTR), regulating p53 translation. Under hypoxia, p53 decreases transactivation and increases transrepression. The mutations outside the DNA binding domain of p53 also contribute to tumor progress, so further studies on p53 should also be focused on this direction. The subterranean blind mole rat Spalax in Israel is a good model for hypoxia-adaptation. The p53 of Spalax mutated in residue 172 and residue 207 from arginine to lysine, conferring it the ability to survive hypoxic conditions. This model indicates that p53 acts as a master gene of diversity formation during evolution.

[1] Ashur-Fabian, O., Avivi, A., Trakhtenbrot, L., Adamsky, K., Cohen, M., Kajakaro, G., Joel, A., Amariglio, N., Nevo, E., Rechavi, G., 2004. Evolution of p53 in hypoxia-stressed Spalax mimics human tumor mutation. Proc. Natl. Acad. Sci. USA, 101(33):12236-12241.

[2] Asker, C., Wiman, K.G., Selivanova, G., 1999. p53-induced apoptosis as a safeguard against cancer. Biochem. Biophys. Res. Commun., 265(1):1-6.

[3] Avivi, A., Ashur-Fabian, O., Amariglio, N., Nevo, E., Rechavi, G., 2005. p53—a key player in tumoral and evolutionary adaptation: a lesson from the Israeli blind subterranean mole rat. Cell Cycle, 4(3):367-372.

[4] Baker, S.J., Fearon, E.R., Nigro, J.M., Hamilton, S.R., Preisinger, A.C., Jessup, J.M., van Tuinen, P., Ledbetter, D.H., Barker, D.F., Nakamura, Y., et al., 1989. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science, 244(4901):217-221.

[5] Banin, S., Moyal, L., Shieh, S., Taya, Y., Anderson, C.W., Chessa, L., Smorodinsky, N.I., Prives, C., Reiss, Y., Shiloh, Y., et al., 1998. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science, 281(5383):1674-1677.

[6] Bargonetti, J., Manfredi, J.J., Chen, X., Marshak, D.R., Prives, C., 1993. A proteolytic fragment from the central region of p53 has marked sequence-specific DNA-binding activity when generated from wild-type but not from oncogenic mutant p53 protein. Genes Dev., 7(12B): 2565-2574.

[7] Canman, C.E., Lim, D.S., Cimprich, K.A., Taya, Y., Tamai, K., Sakaguchi, K., Appella, E., Kastan, M.B., Siliciano, J.D., 1998. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science, 281(5383): 1677-1679.

[8] Chen, D., Li, M., Luo, J., Gu, W., 2003. Direct interaction between HIF-1α and Mdm2 modulate p53 function. J. Biol. Chem., 278(16):13595-13598.

[9] Cho, Y., Gorina, S., Jeffrey, P.D., 1994. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science, 265(5170):346-355.

[10] Clore, G.M., Ernst, J., Clubb, R., Omichinski, J.G., Kennedy, W.M., Sakaguchi, K., Appella, E., Gronenborn, A.M., 1995. Refined solution structure of the oligomerization domain of the tumour suppressor p53. Nat. Struct. Biol., 2(4):321-333.

[11] Davison, T.S., Yin, P., Nie, E., Kay, C., Arrowsmith, C.H., 1998. Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome. Oncogene, 17(5):651-656.

[12] el-Deiry, W.S., 1998. Regulation of p53 downstream genes. Semin. Cancer Biol., 8(5):345-357.

[13] Fels, D.R., Koumenis, C., 2005. HIF-1α and p53: the ODD couple? TRENDS in Biochemical Sciences, 30(8): 426-429.

[14] Gu, J., Kawai, H., Wiederschain, D., Yuan, Z.M., 2001. Mechanism of functional inactivation of a Li-Fraumeni syndrome p53 that has a mutation outside of the DNA-binding domain. Cancer Res., 61(4):1741-1746.

[15] Hammond, E.M., Mandell, D.J., Salim, A., Krieg, A.J., Johnson, T.M., Shirazi, H.A., Attardi, L.D., Giaccia, A.J., 2006. Genome-wide analysis of p53 under hypoxic conditions. Mol. Cell. Biol., 26(9):3492-3504.

[16] Hansson, L.O., Friedler, A., Freund, S., Rudiger, S., Fersht, A.R., 2002. Two sequence motifs from HIF-1α bind to the DNA-binding site of p53. Proc. Natl. Acad. Sci. USA, 99(16):10305-10309.

[17] Haupt, Y., Maya, R., Kazaz, A., Oren, M., 1997. Mdm2 promotes the rapid degradation of p53. Nature, 387(6630): 296-299.

[18] Koumenis, C., Alarcon, R., Hammond, E., Sutphin, P., Hoffman, W., Murphy, M., Derr, J., Taya, Y., Lowe, S.W., Kastan, M., Giaccia, A., 2001. Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation. Mol. Cell. Biol., 21(4):1297-1310.

[19] Kubbutat, M.H., Jones, S.N., Vousden, K.H., 1997. Regulation of p53 stability by Mdm2. Nature, 387(6630):299-303.

[20] Lane, D.P., Crawford, L.V., 1979. T antigen is bound to a host protein in SV40-transformed cells. Nature, 278(5701): 261-263.

[21] Latronico, A.C., Pinto, E.M., Domenice, S., Fragoso, M.C., Martin, R.M., Zerbini, M.C., Lucon, A.M., Mendonca, B.B., 2001. An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. J. Clin. Endocrinol. Metab., 86(10):4970-4973.

[22] Lee, S., Elenbaas, B., Levine, A., Griffith, J., 1995. p53 and its 14 kDa C-terminal domain recognize primary DNA damage in the form of insertion/deletion mismatches. Cell, 81(7):1013-1020.

[23] Miled, C., Pontoglio, M., Garbay, S., Yaniv, M., Weitzman, J.B., 2005. A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network. Cancer Res., 65(12):5096-5104.

[24] Murphy, M., Ahn, J., Walker, K.K., Hoffman, W.H., Evans, R.M., Levine, A.J., George, D.L., 1999. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3A. Genes Dev., 13(19):2490-2501.

[25] Nakamura, Y., Ozaki, T., Niizuma, H., Ohira, M., Kamijo, T., Nakagawara, A., 2007. Functional characterization of a new p53 mutant generated by homozygous deletion in a neuroblastoma cell line. Biochem. Biophys. Res. Commun., 354(4):892-898.

[26] Nieminen, A., Qanungo, S., Schneider, E.A., Jiang, B., Agani, F.H., 2005. Mdm2 and HIF-1α interaction in tumor cells during hypoxia. J. Cell. Physiol., 204(2):364-369.

[27] Nikinmaa, M., Rees, B.B., 2005. Oxygen-dependent gene expression in fishes. Am. J. Physiol. Regul. Integr. Comp. Physiol., 288(5):R1079-R1090.

[28] Pietenpol, J.A., Tokino, T., Thiagalingam, S., el-Deiry, W.S., Kinzler, K.W., Vogelstein, B., 1994. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc. Natl. Acad. Sci. USA, 91(6): 1998-2002.

[29] Resnick, M.A, Inga, A., 2003. Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity. Proc. Natl. Acad. Sci. USA, 100(17):9934-9939.

[30] Sakaguchi, K., Herrera, J.E., Saito, S., Miki, T., Bustin, M., Vassilev, A., Anderson, C.W., Appella, E., 1998. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev., 12(18):2831-2841.

[31] Sánchez-Puig, N., Veprintsev, D.B., Fersht, A.R., 2005. Binding of natively unfolded HIF-1α ODD domain to p53. Mol. Cell, 17(1):11-21.

[32] Shaulsky, G., Goldfinger, N., Ben-Ze'ev, A., Rotter, V., 1990. Nuclear accumulation of p53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol. Cell Biol., 10(12):6565-6577.

[33] Shieh, S.Y., Ikeda, M., Taya, Y., Prives, C., 1997. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell, 91(3):325-334.

[34] Stommel, J.M., Marchenko, N.D., Jimenez, G.S., Moll, U.M., Hope, T.J., Wahl, G.M., 1999. A leucine-rich nuclear export signal in the p53 tetramerization domain regulation of subcellular localization and p53 activity by NES masking. EMBO J., 18(6):1660-1672.

[35] Takagi, M., Absalon, M.J., McLure, K.G., Kastan, M.B., 2005. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell, 123(1):49-63.

[36] Thut, C.J., Chen, J.L., Klemm, R., Tjian, R., 1995. p53 transcriptional activation mediated by coactivators TAFII40 and TAFII60. Science, 267(5194):100-104.

[37] Walker, K.K., Levine, A.J., 1996. Identification of a novel p53 function domain that is necessary for efficient growth suppression. Proc. Natl. Acad. Sci. USA, 93(26): 15335-15340.

[38] Wang, B.Q., Kostrub, C.F., Finkelstein, A., Burton, Z.F., 1993. Production of human RAP30 and RAP74 in bacterial cells. Protein Expr. Purif., 4(3):207-214.

[39] Waterman, M.J., Stavridi, E.S., Waterman, J.L., Halazonetis, T.D., 1998. ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins. Nat. Genet., 19(2):175-178.

[40] Woo, R.A., McLure, K.G., Lees-Miller, S.P., Rancourt, D.E., Lee, P.W., 1998. DNA-dependent protein kinase acts upstream of p53 in response to DNA damage. Nature, 394(6694):700-704.

[41] Zhao, K., Chai, X., Johnston, K., Clements, A., Marmorstein, R., 2001. Crystal structure of the mouse p53 core DNA-binding domain at 2.7 A resolution. J. Biol. Chem., 276(15):12120-12127.