Editing P53 (section)

== Function ==

=== DNA damage and repair ===
p53 plays a role in regulation or progression through the cell cycle, [[apoptosis]], and [[Genome instability|genomic stability]] by means of several mechanisms:
* It can activate [[DNA repair]] proteins when DNA has sustained damage<ref name="Ana et al">{{cite journal | vauthors = Janic A, Abad E, Amelio I | title = Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control? | journal = Cell Death and Differentiation | volume = 32 | issue = 1 | pages = 1–8 | date = January 2025 | pmid = 38379088 | pmc = 11742645 | doi = 10.1038/s41418-024-01259-9 | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref> Thus, it may be an important factor in [[aging]].<ref>{{cite book | vauthors = Gilbert SF |title=Developmental Biology, 10th ed. |publisher=Sinauer Associates, Inc. Publishers |location=Sunderland, MA USA |pages=588}}</ref>
* It can arrest growth by holding the [[cell cycle]] at the [[G1/S transition|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 (i.e., [[programmed cell death]]) if DNA damage proves to be irreparable.
* It is essential for the [[Cellular senescence|senescence]] response to short [[telomere]]s.

[[File:P53 pathways.jpg|300px|right|thumb|'''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 [[p21]] and hundreds of other down-stream genes. p21 (WAF1) binds to the [[G1 phase|G1]]-[[S phase|S]]/[[Cyclin-dependent kinase|CDK]] ([[CDK4]]/[[CDK6]], [[CDK2]], and [[CDK1]]) complexes (molecules important for the [[G1/S transition]] in the cell cycle) inhibiting their activity. {{cn|date=November 2024}}

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.<ref name="urlThe p53 tumor suppressor protein">{{cite book | chapter-url = https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.107 | chapter = Skin and Connective Tissue | title = Genes and Disease |author=National Center for Biotechnology Information |publisher=United States National Institutes of Health |access-date=2008-05-28 |year=1998}}</ref> 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 [[microRNA]]s (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. {{cn|date=November 2024}}

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. {{cn|date=November 2024}}
[[File:Activation of p53 in response to stress signals initiates its transcriptional activity, leading to the activation of cellular protective pathways.jpg|thumb|Activation of p53 in response to stress signals initiates its transcriptional activity, leading to the activation of cellular protective pathways<ref name="Ana et al"/>

p53 binds to the DNA in a tetrameric configuration and promotes the transcription of a wide array of genes. Pictured are key p53 pathways and transcriptional targets regulated by p53 with a specific emphasis on p53-dependent DNA repair genes. BER (base excision repair), NER (nucleotide excision repair), MMR (mismatch repair), HR (homologous recombination), NHEJ (non-homologous end-joining), DDR (DNA damage repair)]]
The p53 and [[Retinoblastoma protein|RB1]] pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other.<ref name="pmid9744267">{{cite journal |vauthors=Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL, Vousden KH |title=p14ARF links the tumour suppressors RB and p53 |journal=Nature |volume=395 |issue=6698 |pages=124–5 |date=September 1998 |pmid=9744267 |doi=10.1038/25867 |bibcode=1998Natur.395..124B |s2cid=4355786}}</ref>

p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to [[sun tanning|tanning]].<ref>{{cite magazine |title=Genome's guardian gets a tan started |url=https://www.newscientist.com/channel/health/mg19325955.800-genomes-guardian-gets-a-tan-started.html |magazine=New Scientist |date=March 17, 2007 |access-date=2007-03-29}}</ref><ref name="pmid17350573">{{cite journal |vauthors=Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, D'Orazio J, Fung CY, Schanbacher CF, Granter SR, Fisher DE |title=Central role of p53 in the suntan response and pathologic hyperpigmentation |journal=Cell |volume=128 |issue=5 |pages=853–64 |date=March 2007 |pmid=17350573 |doi=10.1016/j.cell.2006.12.045 |doi-access=free}}</ref>

=== Stem cells ===
Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life.<ref>{{Cite journal|title=Functions of p53 in pluripotent stem cells|journal=Oxford Academic|date=2020 |volume=11|pages=71–78|doi=10.1007/s13238-019-00665-x |pmid=31691903 | vauthors = Fu X, Wu S, Li B, Xu Y, Liu J |issue=1 |pmc=6949194}}</ref> 

In human [[embryonic stem cell]]s (hESCs)s, p53 is maintained at low inactive levels.<ref name="Jain AK p53">{{cite journal |vauthors=Jain AK, Allton K, Iacovino M, Mahen E, Milczarek RJ, Zwaka TP, Kyba M, Barton MC |title=p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells |journal=PLOS Biology |volume=10 |issue=2 |pages= e1001268 |pmid=22389628 |pmc=3289600 |doi=10.1371/journal.pbio.1001268 |year=2012 |doi-access=free }}</ref> This is because activation of p53 leads to rapid differentiation of hESCs.<ref>{{cite journal |vauthors=Maimets T, Neganova I, Armstrong L, Lako M |title=Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells |journal=Oncogene |volume=27 |issue=40 |pages=5277–87 |date=September 2008 |pmid=18521083 |doi=10.1038/onc.2008.166 |doi-access=free}}</ref> 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.<ref>{{cite journal |vauthors=ter Huurne M, Peng T, Yi G, van Mierlo G, Marks H, Stunnenberg HG |title=Critical role for P53 in regulating the cell cycle of ground state embryonic stem cells |journal=Stem Cell Reports |volume=14 |issue=2 |pages=175–183 |date=February 2020 |pmid=32004494 |doi=10.1016/j.stemcr.2020.01.001 |doi-access=free |pmc=7013234}}</ref>  p53 also activates [[MIR34A|miR-34a]] and [[Mir-145|miR-145]], which then repress the hESCs pluripotency factors, further instigating differentiation.<ref name="Jain AK p53" />

In adult stem cells, p53 regulation is important for maintenance of stemness in [[Stem-cell niche|adult stem cell niches]]. Mechanical signals such as [[hypoxia (medical)|hypoxia]] affect levels of p53 in these niche cells through the [[hypoxia inducible factors]], [[HIF1A|HIF-1α]] and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it.<ref>{{cite journal |vauthors=Das B, Bayat-Mokhtari R, Tsui M, Lotfi S, Tsuchida R, Felsher DW, Yeger H |title=HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells |journal=Stem Cells |volume=30 |issue=8 |pages=1685–95 |date=August 2012 |pmid=22689594 |pmc=3584519 |doi=10.1002/stem.1142}}</ref> 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.<ref>{{cite journal |vauthors=Lake BB, Fink J, Klemetsaune L, Fu X, Jeffers JR, Zambetti GP, Xu Y |title=Context-dependent enhancement of induced pluripotent stem cell reprogramming by silencing Puma |journal=Stem Cells |volume=30 |issue=5 |pages=888–97 |date=May 2012 |pmid=22311782 |pmc=3531606 |doi=10.1002/stem.1054}}</ref><ref>{{cite journal |vauthors=Marión RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA |title=A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity |journal=Nature |volume=460 |issue=7259 |pages=1149–53 |date=August 2009 |pmid=19668189 |pmc=3624089 |doi=10.1038/nature08287 |bibcode=2009Natur.460.1149M}}</ref> 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.<ref>{{cite journal |vauthors=Yun MH, Gates PB, Brockes JP |title=Regulation of p53 is critical for vertebrate limb regeneration |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=110 |issue=43 |pages=17392–7 |date=October 2013 |pmid=24101460 |pmc=3808590 |doi=10.1073/pnas.1310519110 |bibcode=2013PNAS..11017392Y |doi-access=free}}</ref> 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.<ref>{{cite journal |vauthors=Aloni-Grinstein R, Shetzer Y, Kaufman T, Rotter V |title=p53: the barrier to cancer stem cell formation |journal=FEBS Letters |volume=588 |issue=16 |pages=2580–9 |date=August 2014 |pmid=24560790 |doi=10.1016/j.febslet.2014.02.011 |s2cid=37901173 |doi-access=free|bibcode=2014FEBSL.588.2580A }}</ref>

=== Other ===
[[File:P53 and angiogenesis.png|thumb|490x490px|An overview of the molecular mechanism of action of p53 on the angiogenesis<ref name = "Babaei_2021">{{cite journal | vauthors = Babaei G, Aliarab A, Asghari Vostakolaei M, Hotelchi M, Neisari R, Gholizadeh-Ghaleh Aziz S, Bazl MR | title = Crosslink between p53 and metastasis: focus on epithelial-mesenchymal transition, cancer stem cell, angiogenesis, autophagy, and anoikis | journal = Molecular Biology Reports | volume = 48 | issue = 11 | pages = 7545–7557 | date = November 2021 | pmid = 34519942 | doi = 10.1007/s11033-021-06706-1 | s2cid = 237506513 }}</ref>]]
Apart from the cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting [[angiogenesis]].<ref name = "Babaei_2021" /> As tumors grow they need to recruit new blood vessels to supply them, and p53 inhibits that by (i) interfering with regulators of [[tumor hypoxia]] that also affect angiogenesis, such as HIF1 and HIF2, (ii) inhibiting the production of angiogenic promoting factors, and (iii) directly increasing the production of angiogenesis inhibitors, such as [[arresten]].<ref>{{cite journal | vauthors = Teodoro JG, Evans SK, Green MR | title = Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome | journal = Journal of Molecular Medicine | volume = 85 | issue = 11 | pages = 1175–1186 | date = November 2007 | pmid = 17589818 | doi = 10.1007/s00109-007-0221-2 | type = Review | s2cid = 10094554 }}</ref><ref>{{cite journal | vauthors = Assadian S, El-Assaad W, Wang XQ, Gannon PO, Barrès V, Latour M, Mes-Masson AM, Saad F, Sado Y, Dostie J, Teodoro JG | title = p53 inhibits angiogenesis by inducing the production of Arresten | journal = Cancer Research | volume = 72 | issue = 5 | pages = 1270–1279 | date = March 2012 | pmid = 22253229 | doi = 10.1158/0008-5472.CAN-11-2348 | doi-access = free }}</ref>

p53 by regulating [[leukemia inhibitory factor|Leukemia Inhibitory Factor]] has been shown to facilitate [[Implantation (human embryo)|implantation]] in the mouse and possibly human reproduction.<ref name="pmid18046411">{{cite journal | vauthors = Hu W, Feng Z, Teresky AK, Levine AJ | title = p53 regulates maternal reproduction through LIF | journal = Nature | volume = 450 | issue = 7170 | pages = 721–4 | date = November 2007 | pmid = 18046411 | doi = 10.1038/nature05993 | bibcode = 2007Natur.450..721H | s2cid = 4357527 }}</ref>

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,<ref>{{cite journal | vauthors = Borchsenius SN, Daks A, Fedorova O, Chernova O, Barlev NA | title = Effects of mycoplasma infection on the host organism response via p53/NF-κB signaling | journal = Journal of Cellular Physiology | volume = 234 | issue = 1 | pages = 171–180 | date = January 2018 | pmid = 30146800 | doi = 10.1002/jcp.26781 }}</ref> raising the specter of [[carcinogenesis|oncogenic infection]].