Home > A. Molecular pathology > TP53

TP53

Tuesday 30 September 2003

Definition: p53 is a nuclear phospho-protein which, in response to DNA damage, slows progression through the cell cycle and initiates apoptosis if damage is severe. The tumor suppressor gene TP53 is altered in the majority of cancers.

p53 is required for the G1/S checkpoint and is a main component of the G2/M checkpoint. The p53 protein causes cell-cycle arrest and apoptosis. It acts mainly through p21 to cause cell-cycle arrest.

It causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively regulated by MDM2 through a feedback loop.

Structure

The core domain structure consist of a beta-sandwich that serves as a scaffold for two large loops and a loop-sheet-helix motif. The two loops, which are held together in part by a tetrahedrally coordinated zinc atom, and the loop-sheet-helix motif form the DNA binding surface of p53. Residues from the loop-sheet-helix motif interact in the major groove of the DNA, while an arginine from one of the two large loops interacts in the minor groove.

The loops and the loop-sheet-helix motif consist of the conserved regions of the core domain and contain the majority of the p53 mutations identified in tumors.

p53 and DNA damage

The tumour-suppressor protein p53 has an important role in determining the fate of cells following exposure to DNA damage and other types of cellular stresses.

Following these insults, p53 accumulates in the nucleus of cells, where it can act as a transcription factor. Depending on the cell type and the level of damage induced, p53 can increase the survival of exposed cells by transactivating genes encoding DNA-repair enzymes and cell-cycle inhibitors, or induce cells to undergo apoptosis. In either case, both mutagenesis and, subsequently, carcinogenesis are suppressed.

Using human cell lines with specific defects in NER, it has been shown that the triggering mechanism for p53 accumulation and apoptosis following UV-light irradiation is dependent on DNA damage.

Furthermore, the triggering of p53 and apoptosis is not dependent on DNA-repair-induced DNA strand breaks, but rather on persistent lesions specifically in the transcribed strand of active genes.

Studies using human fibroblasts treated with 2-acetylaminofluorene, the polycyclic aromatic hydrocarbon DMBA or cisplatin, which - like UV light - induce bulky DNA lesions, have shown that p53 accumulation and apoptosis are induced at much lower doses in cells that are deficient in the removal of transcription-blocking lesions compared with proficient cells.

The finding that persistent lesions in the transcribed strand of active genes trigger p53 and apoptosis has been confirmed using mouse models with specific genetic defects in GGR or TCR.

p53 and genomic stability

Mutations in TP53, encoding p53, which has been dubbed the ‘guardian of the genome’, are seen in >50% of all sporadic cancers in humans. p53 functions in a highly dynamic and controlled manner; induction of p53 leads to cell cycle arrest in G1 and/or G2, allowing time for DNA repair to take place, but may additionally lead to apoptotic cell death. Moreover, the loss of p53 results in genomic instability.

The p53 tumor suppressor protein has well-established roles in monitoring various types of stress signals by activating specific transcriptional targets that control cell cycle arrest and apoptosis, although some activities are also mediated in a transcription-independent manner.

Post-translational modifications act as epigenetic-like codes for modulating specific functions of p53 in vivo. Deregulation of these modifications might contribute to tumorigenesis.

p53 also regulates cellular metabolism, autophagy and many unconventional tumor suppressor activities.

Pathology

Mutations in TP53, the gene that encodes the tumour suppressor p53, are found in 50% of human cancers. Increased levels of its negative regulators MDM2 and MDM4 (also known as MDMX) downregulate p53 function in many of the rest.

- germline mutations in Li-Fraumeni syndrome (MIM.151623)
- somatic mutations in tumors

  • Inactivation of the tumour suppressor p53 by mutations is the most common defect in cancer cells. The majority of the mutations occur in the core domain which contains the sequence-specific DNA binding activity of the p53 protein (residues 102-292), and they result in loss of DNA binding.
  • Tumour-specific point mutations occur in many forms of human cancer with as many as 50% of cancers containing a p53 mutation. 20% of mutations are concentrated at 5 ’hot-spot’ codons.

- inactivation of p53 protein by HPV-E6 and HPV-E7 oncoproteins

- somatic TP53 inactivation in B-cell lymphomas

  • occurring rarely as an isolated event in DLBCL
  • poor outcome

By tumors

- TP53 in lymphomas (#19500100#)

Animal models

- Mutations of p53 in animal models have been associated with B-cell malignancies.

- In a murine model of impaired DNA repair, mice deficient for both histone 2AX (H2AX) and p53 had markedly increased numbers of B-cell lymphomas and solid tumors.

Links

- P53 signaling pathway at KEGG

See also

- p53-inducible genes (p21, Bax, etc...)
- p53 acetylation
- p53 pathway

Videos

- p53

- Using p53 To Fight Cancer

Reviews

- p53 post-translational modification: deregulated in tumorigenesis. Dai C, Gu W. Trends Mol Med. 2010 Nov;16(11):528-36. PMID: #20932800#

- The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target. Cheung KJ, Horsman DE, Gascoyne RD. Br J Haematol. 2009 Aug;146(3):257-69. PMID: #19500100#

- Fuster JJ, Sanz-González SM, Moll UM, Andrés V. Classic and novel roles of p53: prospects for anticancer therapy. Trends Mol Med. 2007 May;13(5):192-9. PMID: #17383232#

- Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007 Apr;8(4):275-83. PMID: #17380161#

- Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. 2006 Dec;6(12):909-23. PMID: #17128209#

- Moll UM, Wolff S, Speidel D, Deppert W. Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol. 2005 Dec;17(6):631-6. PMID: #16226451#

- Soussi T, Ishioka C, Claustres M, Beroud C. Locus-specific mutation databases: pitfalls and good practice based on the p53 experience. Nat Rev Cancer. 2006 Jan;6(1):83-90. PMID: #16397528#

- Schuler M, Green DR. Transcription, apoptosis and p53: catch-22. Trends Genet. 2005 Mar;21(3):182-7. PMID: #15734577#

- Lu X. p53: a heavily dictated dictator of life and death. Curr Opin Genet Dev. 2005 Feb;15(1):27-33. PMID: #15661530#

- Gudkov AV, Komarova EA. The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer. 2003 Feb;3(2):117-29. PMID: #12563311#

- Hohenstein P, Giles RH. BRCA1 : a scaffold for p53 response ? Trends Genet. 2003 Sep ;19(9):489-94. PMID : #12957542#

- Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer. 2002 Aug;2(8):594-604. PMID: #12154352#

- Smith J. Human Sir2 and the ’silencing’ of p53 activity. Trends Cell Biol. 2002 Sep;12(9):404-6. PMID: #12220851#

- Lane DP, Lain S. Therapeutic exploitation of the p53 pathway. Trends Mol Med. 2002;8(4 Suppl):S38-42. PMID: #11927286#

- Willis AC, Chen X. The promise and obstacle of p53 as a cancer therapeutic agent. Curr Mol Med. 2002 Jun;2(4):329-45. PMID: #12108946#

- Lohrum MA, Vousden KH. Regulation and function of the p53-related proteins: same family, different rules. Trends Cell Biol. 2000 May;10(5):197-202. PMID: #10754563#

- Hartmann A, Blaszyk H, Kovach JS, Sommer SS. The molecular epidemiology of p53 gene mutations in human breast cancer. Trends Genet. 1997 Jan;13(1):27-33. PMID: #9009845#

- Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323-31. PMID: #9039259#

Portfolio

  • P53 signaling pathway at KEGG
  • ATM molecular pathway.
  • DNA Damage Induced 14-3-3Sigma Signaling