Negative regulation of p53-induced senescence by N-WASP is crucial for DMBA/TPA-induced skin tumor formation
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Negative regulation of p53-induced senescence by N-WASP is crucial for DMBA/TPA-induced skin tumor formation. / Li, Hui; Petersen, Simon; Garcia Mariscal, Alberto; Brakebusch, Cord.
I: Cancer Research, Bind 79, Nr. 9, 01.05.2019, s. 2167-2181.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Negative regulation of p53-induced senescence by N-WASP is crucial for DMBA/TPA-induced skin tumor formation
AU - Li, Hui
AU - Petersen, Simon
AU - Garcia Mariscal, Alberto
AU - Brakebusch, Cord
N1 - Copyright ©2019, American Association for Cancer Research.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - Mice with a keratinocyte-restricted deletion of the actin-polymerization promoting molecule N-WASP display cyclic hair loss and skin inflammation. Here we showed that these mice were also resistant to DMBA/TPA induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator DNMT1 and increased expression of the senescence marker p16Ink4a in N-WASP-deficient epidermis. Moreover, primary N-WASP null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP-null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases G9a/GLP and the DNA methyltransferase DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP-independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53-induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes.
AB - Mice with a keratinocyte-restricted deletion of the actin-polymerization promoting molecule N-WASP display cyclic hair loss and skin inflammation. Here we showed that these mice were also resistant to DMBA/TPA induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator DNMT1 and increased expression of the senescence marker p16Ink4a in N-WASP-deficient epidermis. Moreover, primary N-WASP null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP-null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases G9a/GLP and the DNA methyltransferase DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP-independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53-induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes.
U2 - 10.1158/0008-5472.CAN-18-1253
DO - 10.1158/0008-5472.CAN-18-1253
M3 - Journal article
C2 - 30894371
VL - 79
SP - 2167
EP - 2181
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 9
ER -
ID: 216917241