User talk:adrg

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Tumor protein p53
P53.png
PDB rendering based on 1TUP: P53 complexed with DNA[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TP53 ; BCC7; LFS1; P53; TRP53
External IDs OMIM191170 MGI98834 HomoloGene460 ChEMBL: 4096 GeneCards: TP53 Gene
RNA expression pattern
PBB GE TP53 201746 at.png
PBB GE TP53 211300 s at.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 7157 22059
Ensembl ENSG00000141510 ENSMUSG00000059552
UniProt P04637 P02340
RefSeq (mRNA) NM_000546 NM_001127233
RefSeq (protein) NP_000537 NP_001120705
Location (UCSC) Chr 17:
7.57 – 7.59 Mb
Chr 11:
69.58 – 69.59 Mb
PubMed search [1] [2]

p53 (also known as protein 53 or tumor protein 53), is a transcription factor encoded by the TP53 gene. p53 is important in multicellular organisms, where it regulates the cell cycle and thus functions as a tumor suppressor that is involved in preventing cancer.


Amino Acids[edit]

1-10 11-20 21-30 31-40 41-50
meepqsdpsv epplsqetfs dlwkllpenn vlsplpsqam ddlmlspddi
eqwftedpgp deaprmpeaa prvapapaap tpaapapaps wplsssvpsq
ktyqgsygfr lgflhsgtak svtctyspal nkmfcqlakt cpvqlwvdst
pppgtrvram aiykqsqhmt evvrrcphhe rcsdsdglap pqhlirvegn
lrveylddrn tfrhsvvvpy eppevgsdct tihynymcns scmggmnrrp
iltiitleds sgnllgrnsf evrvcacagr drrteeenlr kkgephhelp
pgstkralpn ntssspqpkk kpldgeyftl qirgrerfem frelnealel
kdaqagkepg gsrahsshlk skkgqstsrh kklmfktegp dsd


Other Names[edit]

  • Official protein name: Cellular tumor antigen p53
  • Tumor suppressor p53
  • Transformation-related protein 53 (TRP53)
  • Phosphoprotein p53
  • Antigen NY-CO-13

Coding Genes[edit]

In humans, p53 is encoded by the TP53 gene located on the short arm of chromosome 17 (17p13.1). coded_by="DQ892492.2:23..1204"

The gene is on different locations in other animals:

  • Mouse - chromosome 11
  • Rat - chromosome 10
  • Dog - chromosome 5
  • Pig - chromosome 12

(Italics are used to distinguish the TP53 gene name from the protein it encodes.)

Structure/Domains[edit]

Human p53 is 393 amino acids long and has seven domains:

  • An N-terminal transcription-activation domain (TAD), also known as activation domain 1 (AD1) which activates transcription factors: residues 1-42.
  • An activation domain 2 (AD2) important for apoptotic activity: residues 43-63.
  • A Proline rich domain important for the apoptotic activity of p53: residues 80-94.
  • A central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 100-300.
  • A nuclear localization signalling domain, residues 316-325.
  • A homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo.
  • A C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393.

Post-translational Modification[edit]

Position Sequence Kinase PubMed
S9 MEEPQSDPSVEPPLSQETF --- 11875057
S15 QSDPSVEPPLSQETFSDLWKL ATM;DNA-PK;RSK-2 11875057;10446957
T18 PSVEPPLSQETFSDLWKLLPE CK1_group 10606744
S20 VEPPLSQETFSDLWKLLPENN CHK2 12111733;10801407;15489221;15254178
S33 WKLLPENNVLSPLPSQAMDDL GSK-3_group;CDK7;CDK_group 11483158;9372954
S37 PENNVLSPLPSQAMDDLMLSP DNA-PK 11483158
S46 PSQAMDDLMLSPDDIEQWFTE HIPK2 11875057;16729035
T55 LSPDDIEQWFTEDPGPDEAPR MAPK_group 11409876
S215 YLDDRNTFRHSVVVPYEPPEV Aurora A 15469940
S315 KRALPNNTSSSPQPKKKPLDG Aurora A;CDK_group 92065884;14702041
S371 GSRAHSSHLKSKKGQSTSRHK CDK7 9315650
S376 SSHLKSKKGQSTSRHKKLMFK CDK7 9315650
S378 HLKSKKGQSTSRHKKLMFKTE CDK7 9315650
S392 KLMFKTEGPDSD CK2_group;CDK7;EIF2AK2 10747897;10348343;9315650;16083285

Transcription/Translation[edit]

Protein Interaction[edit]

Interactor Description Species
ATM Ataxia Telangiectasia Mutated. Protein kinase that phosphorylates p53, Chk2 and histone H2AX. Homo sapiens
MAPK8 Mitogen-activated protein kinase 8;c-Jun N-terminal kinase 1; JNK1 alpha/beta protein kinase; stress-activated protein kinase JNK1. Homo sapiens

Homology Sequences[edit]

Pre-computed BLAST results for: gi|123983354|gb|ABM83418.1 tumor protein p53 (Li-Fraumeni syndrome) [synthetic construct]
Matching gis: 13097807;
Total (Score>106) : 942 hits in 936 proteins in 114 species
Selected: 2 hits in 2 proteins in 2 species Filter: Min Score: 106 | Included taxons: Plants;

Score Accession ID Length Protein Description
1159 AAT42177 224 putative tumor protein p53 [Zea mays]
107 AAA02923 300 structural wall protein

Functional significance[edit]

p53 has many anti-cancer mechanisms:

  • It can activate DNA repair proteins when DNA has sustained damage.
  • It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.)
  • It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irreparable.
p53 pathway: In a normal cell p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stress, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will either induce a cell cycle arrest to allow repair and survival of the cell or apoptosis to discard the damage cell. How p53 makes this choice is currently unknown.

Regulation of p53 activity[edit]

p53 becomes activated in response to a myriad of stress types, which include but is not limited to DNA damage (induced by either UV, IR or chemical agents,such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion and deregulated oncogene expression. This activation is marked by two major events. Firstly, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Secondly, a conformational change forces p53 to take on an active role as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.

The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc... A second group of protein kinases (ATR, ATM, Chk1, Chk2, DNA-PK, CAK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress.

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 binds to p53 and transports it from the nucleus to the cytosol where it becomes degraded by the proteasome. Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53 which prevents Mdm2-binding even more. Trancriptional coactivators, like p300 or PCAF, then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.


Readings[edit]

  • Cheng R, Ford BL, O'Neal PE, Mathews CZ, Bradford CS, Thongtan T, Barnes DW, Hendricks JD, Bailey GS. (1997, Jun.). "Zebrafish (Danio rerio) p53 tumor suppressor gene: cDNA sequence and expression during embryogenesis.". Mol Mar Biol Biotechnol. 6 (2): 88–97. PMID 9200835. 
  • Lee KC, Goh WL, Xu M, Kua N, Lunny D, Wong JS, Coomber D, Vojtesek B, Lane EB, Lane DP. (2008, Jan.). "Detection of the p53 response in zebrafish embryos using new monoclonal antibodies.". Oncogene. 27 (5): 629–40. PMID 17684488. 



Adrg (talk) 00:50, 20 July 2008 (UTC)

  1. ^ Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994). "Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations". Science 265 (5170): 346–55. doi:10.1126/science.8023157. PMID 8023157.