p53

Source: Wikipedia, the free encyclopedia.
(Redirected from
P53 protein
)
For other uses, see P53 (disambiguation).
TP53
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000141510

ENSMUSG00000059552

UniProt

P04637

P02340

RefSeq (mRNA)

NM_001127233
NM_011640

RefSeq (protein)

NP_001120705
NP_035770

Location (UCSC)Chr 17: 7.66 – 7.69 MbChr 11: 69.47 – 69.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often spoken of as, a single protein) are crucial in vertebrates, where they prevent cancer formation.[5] As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.[6] Hence TP53[note 1] is classified as a tumor suppressor gene.[7][8][9][10][11]

The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation.[5] TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.[12] In addition to the full-length protein, the human TP53 gene encodes at least 12 protein isoforms.[13]

Gene

In humans, the TP53 gene is located on the short arm of

mammals
for which complete genome data are available.

Human TP53 gene

In humans, a common

codon position 72 of exon 4. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer.[16] A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.[17] A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer.[18] One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women.[19] A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.[20]

Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk[21] and endometrial cancer risk.[22] A 2011 study of a Brazilian birth cohort found an association between the non-mutant arginine TP53 and individuals without a family history of cancer.[23] Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.[24]

Function

DNA damage and repair

p53 plays a role in regulation or progression through the cell cycle, apoptosis, and genomic stability by means of several mechanisms:

p53 pathway: In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

WAF1/CIP1 encodes for

CDK1) complexes (molecules important for the G1/S transition
in the cell cycle) inhibiting their activity.

When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.[26] Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.

The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity, thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein.

The p53 and RB1 pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other.[27]

p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning.[28][29]

Stem cells

Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life.

In human embryonic stem cells (hESCs)s, p53 is maintained at low inactive levels.[30] This is because activation of p53 leads to rapid differentiation of hESCs.[31] Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. Work in mouse embryonic stem cells has recently shown however that the expression of P53 does not necessarily lead to differentiation.[32] p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation.[30]

In adult stem cells, p53 regulation is important for maintenance of stemness in

hypoxia inducible factors, HIF-1α and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it.[33] Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency than normal cells.[34][35] Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders.[36] p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous.[37]

Other

An overview of the molecular mechanism of action of p53 on the angiogenesis.[38]

Apart from the cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting

arresten.[39][40]

p53 by regulating

implantation in the mouse and possibly humans reproduction.[41]

The immune response to infection also involves p53 and NF-κB. Checkpoint control of the cell cycle and of apoptosis by p53 is inhibited by some infections such as Mycoplasma bacteria,[42] raising the specter of oncogenic infection.

Regulation

p53 acts as a cellular stress sensor. It is normally kept at low levels by being constantly marked for degradation by the

DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,[44] osmotic shock, ribonucleotide depletion, viral lung infections[45] and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated 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

p14ARF
.

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called

feedback loop. p53 levels can show oscillations (or repeated pulses) in response to certain stresses, and these pulses can be important in determining whether the cells survive the stress, or die.[46]

MI-63 binds to MDM2, reactivating p53 in situations where p53's function has become inhibited.[47]

A ubiquitin specific protease,

ubiquitin ligase pathway. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.[48]

Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result in a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells.

USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.[49]

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. Phosphorylation also allows for binding of transcriptional coactivators, like

Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.[50]
Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.

Role in disease

Overview of signal transduction pathways involved in apoptosis
p53 immunostain
.

If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as

Li-Fraumeni syndrome
.

The TP53 gene can also be modified by

deletion of the TP53 gene.[51] Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype.[52]

Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging.

adenovirus.[56]

Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example,

cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.[57]

The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation (see a stochastic model of this process in [58]). The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.[59]

This image shows different patterns of p53 expression in endometrial cancers on chromogenic immunohistochemistry, whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation:[60]

  • Wild-type, upper left: Endometrial endometrioid carcinoma showing normal wild-type pattern of p53 expression with variable proportion of tumor cell nuclei staining with variable intensity. Note, this wild-type pattern should not be reported as "positive," because this is ambiguous reporting language.
  • Overexpression, upper right: Endometrial endometrioid carcinoma, grade 3, with overexpression, showing strong staining in virtually all tumor cell nuclei, much stronger compared with the internal control of fibroblasts in the center. Note, there is some cytoplasmic background indicating that this staining is quite strong but this should not be interpreted as abnormal cytoplasmic pattern.
  • Complete absence, lower left: Endometrial serous carcinoma showing complete absence of p53 expression with internal control showing moderate to strong but variable staining. Note, wild-type pattern in normal atrophic glands at 12 and 6 o'clock.
  • Both cytoplasmic and nuclear, lower right: Endometrial endometrioid carcinoma showing cytoplasmic p53 expression with internal control (stroma and normal endometrial glands) showing nuclear wild-type pattern. The cytoplasmic pattern is accompanied by nuclear staining of similar intensity.
urothelial carcinoma. Overexpression is seen in 75% of low-grade urothelial carcinomas and only 10% of PUNLMP.[61][62]

Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13.[63]

One study found that p53 and

Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML.[64][65]

Experimental analysis of p53 mutations

Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional effects.[59]

The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recent studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provide cancer stem cell potential in different tissues.[11][66][67][68] TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.[69]

The dynamics of p53 proteins, along with its antagonist

mathematically modelled.[71][72] Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery
.

Discovery

p53 was identified in 1979 by

Memorial Sloan-Kettering Cancer Center, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The name p53 was given in 1979 describing the apparent molecular mass
.

The TP53 gene from the mouse was first cloned by Peter Chumakov of The Academy of Sciences of the USSR in 1982,[73] and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science).[74][75] The human TP53 gene was cloned in 1984[7] and the full length clone in 1985.[76]

It was initially presumed to be an

mRNA. Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University.[77][78] p53 went on to be identified as a transcription factor by Guillermina Lozano working at MD Anderson Cancer Center.[79]

Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.[80] In a series of publications in 1991–92, Michael Kastan of Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.[81]

In 1993, p53 was voted molecule of the year by Science magazine.[82]

Structure

A schematic of the known protein domains in p53. (NLS = Nuclear Localization Signal).
domains
:

  1. an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes.[83]
  2. activation domain 2 (AD2) important for apoptotic activity: residues 43–63.
  3. MAPK
    : residues 64–92.
  4. central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 102–292. This region is responsible for binding the p53 co-repressor LMO3.[84]
  5. Nuclear Localization Signaling (NLS) domain, residues 316–325.
  6. homo-oligomerisation domain (OD): residues 307–355. Tetramerization is essential for the activity of p53 in vivo.
  7. C-terminal involved in downregulation of DNA binding of the central domain: residues 356–393.[85]

Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are

wild-type
p53, and prevent them from activating transcription. Therefore, OD mutations have a dominant negative effect on the function of p53.

Wild-type p53 is a

unstructured regions that function in a synergistic manner.[86]

kilodalton (kDa) protein. However, the actual mass of the full-length p53 protein (p53α) based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is.[87]

Isoforms

As with 95% of human genes, TP53 encodes more than one protein. All these p53 proteins are called the p53 isoforms.[5] These proteins range in size from 3.5 to 43.7 kDa. Several isoforms were discovered in 2005, and so far 12 human p53 isoforms have been identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ). Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone.[11]

The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N-terminus, there are first the amino-terminal transcription-activation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes. This domain is followed by the proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a proline and X can be any amino acid). It is required among others for p53 mediated apoptosis.[88] Some isoforms lack the proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene.[66] Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding. The C-terminus domain completes the protein. It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain.

The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which lack the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms.[11]

Due to the

isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene (refer to section Experimental analysis of p53 mutations
for more details).

Interactions

p53 has been shown to

interact
with:

See also

Notes

  1. ^ italics are used to denote the TP53 gene name and distinguish it from the protein it encodes

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  172. PMID 9565608
    .
  173. PMID 11583632
    .
  174. PMID 12388558
    .
  175. S2CID 4311658
    .
  176. S2CID 21331603
    .
  177. PMID 11551930
    .
  178. S2CID 24106070
    .
  179. PMID 9010216
    .
  180. PMID 14500729
    .
  181. PMID 11080164
    .
  182. S2CID 13480833
    .
  183. ^
    PMID 18309296
    .
  184. PMID 18206965
    .
  185. S2CID 1770399
    .
  186. PMID 8617246
    .
  187. PMID 9380510
    .
  188. PMID 12654245
    .
  189. PMID 19043414
    .
  190. S2CID 23482723
    .
  191. PMID 11751427
    .
  192. PMID 15178678
    .
  193. ^
    PMID 10961991
    .
  194. ^
    PMID 18583933
    .
  195. ^
    PMID 11950834
    .
  196. PMID 11704667
    .
  197. PMID 1465435
    .
  198. PMID 10359315
    .
  199. PMID 12226108
    .
  200. PMID 8816502
    .
  201. PMID 16839873
    .
  202. PMID 10468612
    .
  203. PMID 11805286
    .
  204. ^
    PMID 10666337
    .
  205. PMID 12110597
    .
  206. PMID 14978302
    .
  207. PMID 15611139
    .
  208. PMID 11877378
    .
  209. PMID 12351827
    .
  210. ^
    PMID 8016121
    .
  211. PMID 8668206
    .
  212. PMID 12851404
    .
  213. PMID 11511362
    .
  214. PMID 11172000
    .
  215. PMID 12640129
    .
  216. PMID 8921390
    .
  217. PMID 11853669
    .
  218. PMID 18632619
    .
  219. PMID 18566590
    .
  220. PMID 18382127
    .
  221. PMID 18359851
    .
  222. S2CID 8023403
    .
  223. S2CID 4389394
    .
  224. PMID 11427532
    .
  225. PMID 11058590
    .
  226. S2CID 19222684
    .
  227. PMID 20388804
    .
  228. S2CID 26600934
    .
  229. PMID 11251186
    .
  230. PMID 11416144
    .
  231. PMID 19221490
    .
  232. PMID 30640591
    .

External links

Wikimedia Commons has media related to Tumor suppressor protein p53.
Retrieved from "https://en.wikipedia.org/w/index.php?title=P53&oldid=1219255543"