Regulation of TP53 Activity through Phosphorylation

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Homo sapiens
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Phosphorylation of TP53 (p53) at the N-terminal serine residues S15 and S20 plays a critical role in protein stabilization as phosphorylation at these sites interferes with binding of the ubiquitin ligase MDM2 to TP53. Several different kinases can phosphorylate TP53 at S15 and S20. In response to double strand DNA breaks, S15 is phosphorylated by ATM (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998), and S20 by CHEK2 (Chehab et al. 1999, Chehab et al. 2000, Hirao et al. 2000). DNA damage or other types of genotoxic stress, such as stalled replication forks, can trigger ATR-mediated phosphorylation of TP53 at S15 (Lakin et al. 1999, Tibbetts et al. 1999) and CHEK1-mediated phosphorylation of TP53 at S20 (Shieh et al. 2000). In response to various types of cell stress, NUAK1 (Hou et al. 2011), CDK5 (Zhang et al. 2002, Lee et al. 2007, Lee et al. 2008), AMPK (Jones et al. 2005) and TP53RK (Abe et al. 2001, Facchin et al. 2003) can phosphorylate TP53 at S15, while PLK3 (Xie, Wang et al. 2001, Xie, Wu et al. 2001) can phosphorylate TP53 at S20.

Phosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2 (Taira et al. 2007, Taira et al. 2010). TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1 (D'Orazi et al. 2002, Hofmann et al. 2002, Tomasini et al. 2003). CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death (Lee et al. 2007).

MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling (Sun et al. 2007).

NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes (Hou et al. 2011). S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).

The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) (Katayama et al. 2004) and CDK2 (Luciani et al. 2000). Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID (Li et al. 2004).

Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism (Wu et al. 2011). A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation (Gully et al. 2012).

Literature References
PubMed ID Title Journal Year
22611192 Aurora B kinase phosphorylates and instigates degradation of p53

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Proc. Natl. Acad. Sci. U.S.A. 2012
17591690 Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death

Kim, HS, Lee, SJ, Lee, JH, Kim, KT

J. Cell. Sci. 2007
17349958 DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage

Miki, Y, Nihira, K, Taira, N, Yoshida, K, Yamaguchi, T

Mol. Cell 2007
15053879 Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression

Sheppard, HM, Li, HH, Li, AG, Liu, X

Mol. Cell 2004
15866171 AMP-activated protein kinase induces a p53-dependent metabolic checkpoint

Mu, J, Plas, DR, Birnbaum, MJ, Buzzai, M, Jones, RG, Kubek, S, Thompson, CB, Xu, Y

Mol. Cell 2005
10710310 DNA damage-induced activation of p53 by the checkpoint kinase Chk2.

Hirao, A, Elledge, SJ, Mak, TW, Yoshida, H, Liu, D, Matsuoka, S, Wakeham, A, Ruland, J, Kong, YY

Science 2000
10673501 The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites.

Tamai, K, Taya, Y, Ahn, J, Prives, C, Shieh, SY

Genes Dev 2000
10570149 Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage

Halazonetis, TD, Malikzay, A, Stavridi, ES, Chehab, NH

Proc. Natl. Acad. Sci. U.S.A. 1999
12064478 Cdk5 phosphorylates p53 and regulates its activity

Krishnamurthy, PK, Johnson, GV, Zhang, J

J. Neurochem. 2002
20959462 Aurora B interacts with NIR-p53, leading to p53 phosphorylation in its DNA-binding domain and subsequent functional suppression

Wu, L, Zhao, Y, Jain, A, Ma, CA

J. Biol. Chem. 2011
11447225 Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3

Wang, Q, Dai, W, Wu, H, Lu, L, Xie, S, Cogswell, J, Jhanwar-Uniyal, M

J. Biol. Chem. 2001
11551930 Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway

Husain, I, Wang, Q, Stambrook, P, Dai, W, Wu, H, Xie, S, Conn, C, Cogswell, JP, Jhanwar-Uniyal, M

J. Biol. Chem. 2001
10673500 Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.

Appel, M, Halazonetis, TD, Chehab, NH, Malikzay, A

Genes Dev 2000
18490454 Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress

Choi, YH, Lee, JH, Kim, KT, Kim, W, Jeong, MW

J. Biol. Chem. 2008
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Hutchins, JR, Hupp, TR, Zheleva, D, Luciani, MG

J. Mol. Biol. 2000
12393879 p53 serine 392 phosphorylation increases after UV through induction of the assembly of the CK2.hSPT16.SSRP1 complex

Lu, H, Keller, DM

J. Biol. Chem. 2002
11239457 A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1

Goodman, R, Shu, H, Lu, H, Zhao, Y, Kapoor, M, Zhang, QH, Keller, DM, Lozano, G, Wang, Y, Zeng, X

Mol. Cell 2001
9843217 ATM associates with and phosphorylates p53: mapping the region of interaction.

Gatei, M, Hobson, K, Taya, Y, Kozlov, S, Scott, S, Keating, KE, Lees-Miller, SP, Lavin, MF, Gabrielli, B, Khanna, KK, Chan, D

Nat Genet 1998
11546806 Cloning and characterization of a p53-related protein kinase expressed in interleukin-2-activated cytotoxic T-cells, epithelial tumor cell lines, and the testes

Nikawa, J, Abe, Y, Enomoto, Y, Matsumoto, S, Nezu, K, Wei, S, Ueda, N, Shigemoto, K, Miyoshi, A, Hitsumoto, Y, Kito, K

J. Biol. Chem. 2001
9733514 Enhanced phosphorylation of p53 by ATM in response to DNA damage.

Shiloh, Y, Taya, Y, Reiss, Y, Ziv, Y, Smorodinsky, NI, Prives, C, Anderson, CW, Chessa, L, Moyal, L, Shieh, S, Banin, S

Science 1998
12851404 TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity

Malissen, B, Tomasini, R, Carrier, A, Dusetti, NJ, Isnardon, D, Samir, AA, Cecchinelli, B, Soddu, S, Iovanna, JL, Dagorn, JC

J. Biol. Chem. 2003
19965871 ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage

Yamamoto, H, Miki, Y, Taira, N, Yoshida, K, Yamaguchi, T

J. Biol. Chem. 2010
21317932 A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

Liu, JE, Liu, ZY, Liu, W, Sun, ZY, Liu, CY, Hou, X

Oncogene 2011
11780126 Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis

Higashimoto, Y, Piaggio, G, Cecchinelli, B, Soddu, S, Marchetti, A, Saito, S, Gostissa, M, Manni, I, Del Sal, G, D'Orazi, G, Fanciulli, M, Appella, E, Bruno, T, Coen, S

Nat. Cell Biol. 2002
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Appella, E, Siliciano, JD, Kastan, MB, Tamai, K, Taya, Y, Sakaguchi, K, Lim, DS, Canman, CE

Science 1998
10435622 The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53

Jackson, SP, Hann, BC, Lakin, ND

Oncogene 1999
11740489 Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2

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Nat. Cell Biol. 2002
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