Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response
© 2024. The Author(s)..
Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
---|---|
Enthalten in: |
Nature communications - 15(2024), 1 vom: 02. Jan., Seite 180 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Zhao, Mei [VerfasserIn] |
---|
Links: |
---|
Themen: |
9007-49-2 |
---|
Anmerkungen: |
Date Completed 05.01.2024 Date Revised 10.02.2024 published: Electronic Citation Status MEDLINE |
---|
doi: |
10.1038/s41467-023-44239-2 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM366579738 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM366579738 | ||
003 | DE-627 | ||
005 | 20240210233037.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240108s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/s41467-023-44239-2 |2 doi | |
028 | 5 | 2 | |a pubmed24n1287.xml |
035 | |a (DE-627)NLM366579738 | ||
035 | |a (NLM)38167338 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Zhao, Mei |e verfasserin |4 aut | |
245 | 1 | 0 | |a Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 05.01.2024 | ||
500 | |a Date Revised 10.02.2024 | ||
500 | |a published: Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2024. The Author(s). | ||
520 | |a Inactivating TP53 mutations leads to a loss of function of p53, but can also often result in oncogenic gain-of-function (GOF) of mutant p53 (mutp53) proteins which promotes tumor development and progression. The GOF activities of TP53 mutations are well documented, but the mechanisms involved remain poorly understood. Here, we study the mutp53 interactome and find that by targeting minichromosome maintenance complex components (MCMs), GOF mutp53 predisposes cells to replication stress and chromosomal instability (CIN), leading to a tumor cell-autonomous and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Consequently, GOF mutp53-MCMs-CIN-cytosolic DNA-cGAS-STING-NC-NF-κB signaling promotes tumor cell metastasis and an immunosuppressive tumor microenvironment through antagonizing interferon signaling and regulating genes associated with pro-tumorigenic inflammation. Our findings have important implications for understanding not only the GOF activities of TP53 mutations but also the genome-guardian role of p53 and its inactivation during tumor development and progression | ||
650 | 4 | |a Journal Article | |
650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
650 | 7 | |a NF-kappa B |2 NLM | |
650 | 7 | |a DNA |2 NLM | |
650 | 7 | |a 9007-49-2 |2 NLM | |
650 | 7 | |a Nucleotidyltransferases |2 NLM | |
650 | 7 | |a EC 2.7.7.- |2 NLM | |
650 | 7 | |a Interferons |2 NLM | |
650 | 7 | |a 9008-11-1 |2 NLM | |
700 | 1 | |a Wang, Tianxiao |e verfasserin |4 aut | |
700 | 1 | |a Gleber-Netto, Frederico O |e verfasserin |4 aut | |
700 | 1 | |a Chen, Zhen |e verfasserin |4 aut | |
700 | 1 | |a McGrail, Daniel J |e verfasserin |4 aut | |
700 | 1 | |a Gomez, Javier A |e verfasserin |4 aut | |
700 | 1 | |a Ju, Wutong |e verfasserin |4 aut | |
700 | 1 | |a Gadhikar, Mayur A |e verfasserin |4 aut | |
700 | 1 | |a Ma, Wencai |e verfasserin |4 aut | |
700 | 1 | |a Shen, Li |e verfasserin |4 aut | |
700 | 1 | |a Wang, Qi |e verfasserin |4 aut | |
700 | 1 | |a Tang, Ximing |e verfasserin |4 aut | |
700 | 1 | |a Pathak, Sen |e verfasserin |4 aut | |
700 | 1 | |a Raso, Maria Gabriela |e verfasserin |4 aut | |
700 | 1 | |a Burks, Jared K |e verfasserin |4 aut | |
700 | 1 | |a Lin, Shiaw-Yih |e verfasserin |4 aut | |
700 | 1 | |a Wang, Jing |e verfasserin |4 aut | |
700 | 1 | |a Multani, Asha S |e verfasserin |4 aut | |
700 | 1 | |a Pickering, Curtis R |e verfasserin |4 aut | |
700 | 1 | |a Chen, Junjie |e verfasserin |4 aut | |
700 | 1 | |a Myers, Jeffrey N |e verfasserin |4 aut | |
700 | 1 | |a Zhou, Ge |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 15(2024), 1 vom: 02. Jan., Seite 180 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
773 | 1 | 8 | |g volume:15 |g year:2024 |g number:1 |g day:02 |g month:01 |g pages:180 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-023-44239-2 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 15 |j 2024 |e 1 |b 02 |c 01 |h 180 |