TAp63γ is the primary isoform of TP63 for tumor suppression but not development
Abstract TP63 is expressed as TAp63 and ΔNp63 from the P1 and P2 promoters, respectively. While TAp63 and ΔNp63 are expressed as three TAp63α/β/γ and ΔNp63α/β/γ due to alternative splicing, only p63α (TA and ΔN) and p63γ (TA and ΔN) proteins are found to be detectable and likely to be responsible fo...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02326-x |
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| author | Xinbin Chen Wenqiang Sun Xiangmudong Kong Xin Ming Yanhong Zhang Wensheng Yan Shakur Mohibi Mingyi Chen Keith Mitchell Jin Zhang |
| author_facet | Xinbin Chen Wenqiang Sun Xiangmudong Kong Xin Ming Yanhong Zhang Wensheng Yan Shakur Mohibi Mingyi Chen Keith Mitchell Jin Zhang |
| author_sort | Xinbin Chen |
| collection | DOAJ |
| description | Abstract TP63 is expressed as TAp63 and ΔNp63 from the P1 and P2 promoters, respectively. While TAp63 and ΔNp63 are expressed as three TAp63α/β/γ and ΔNp63α/β/γ due to alternative splicing, only p63α (TA and ΔN) and p63γ (TA and ΔN) proteins are found to be detectable and likely to be responsible for p63-dependent activity. Previous studies implied and/or demonstrated that TAp63α, which contains an N-terminal activation domain conserved in p53, functions as a tumor suppressor by regulating an array of genes for growth suppression. By contrast, ΔNp63α, which also contains an N-terminal activation domain but is different from that in TAp63, regulates a unique set of genes and functions as a master regulator for development of epidermis and other stratified epithelial tissues. However, the biological function of p63γ is largely unexplored. To explore this, we generated a mouse model in that exon 10’, a coding exon specific for p63γ, was deleted by CRISPR-cas9. We showed that mice deficient in p63γ are viable and futile, which is different from mice deficient in total TP63 or p63α. Like TAp63-deficient mice, p63γ-deficient mice have a short lifespan and are prone to spontanenous tumors. Additionally, loss of p63γ shortens the lifespan of tumor-free mice potentially via increased cellular senescence. Moreover, mice deficient in p63γ are prone to chronic inflammation in multiple organs and liver steatosis potentially via altered lipid metabolism. Single-cell RNA-seq revealed that loss of p63γ increases the expression of SCD1, a rate-limiting enzyme for synthesis of monounsaturated fatty acids, leading to altered lipid homeostasis. Together, our data indicate that TP63γ is the primary isoform of TP63 for tumor suppression but not development by maintaining normal inflammatory response and lipid homeostasis. |
| format | Article |
| id | doaj-art-ca23bfde42934cf8abffa44f07b2e97d |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-ca23bfde42934cf8abffa44f07b2e97d2025-02-09T12:12:32ZengNature Publishing GroupCell Death Discovery2058-77162025-02-011111910.1038/s41420-025-02326-xTAp63γ is the primary isoform of TP63 for tumor suppression but not developmentXinbin Chen0Wenqiang Sun1Xiangmudong Kong2Xin Ming3Yanhong Zhang4Wensheng Yan5Shakur Mohibi6Mingyi Chen7Keith Mitchell8Jin Zhang9Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaComparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaComparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaComparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaComparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaComparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaComparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaDepartment of Pathology, University of Texas Southwestern Medical CenterDepartment of Physiology and Membrane Biology, University of California Davis School of Medicine, DavisComparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of CaliforniaAbstract TP63 is expressed as TAp63 and ΔNp63 from the P1 and P2 promoters, respectively. While TAp63 and ΔNp63 are expressed as three TAp63α/β/γ and ΔNp63α/β/γ due to alternative splicing, only p63α (TA and ΔN) and p63γ (TA and ΔN) proteins are found to be detectable and likely to be responsible for p63-dependent activity. Previous studies implied and/or demonstrated that TAp63α, which contains an N-terminal activation domain conserved in p53, functions as a tumor suppressor by regulating an array of genes for growth suppression. By contrast, ΔNp63α, which also contains an N-terminal activation domain but is different from that in TAp63, regulates a unique set of genes and functions as a master regulator for development of epidermis and other stratified epithelial tissues. However, the biological function of p63γ is largely unexplored. To explore this, we generated a mouse model in that exon 10’, a coding exon specific for p63γ, was deleted by CRISPR-cas9. We showed that mice deficient in p63γ are viable and futile, which is different from mice deficient in total TP63 or p63α. Like TAp63-deficient mice, p63γ-deficient mice have a short lifespan and are prone to spontanenous tumors. Additionally, loss of p63γ shortens the lifespan of tumor-free mice potentially via increased cellular senescence. Moreover, mice deficient in p63γ are prone to chronic inflammation in multiple organs and liver steatosis potentially via altered lipid metabolism. Single-cell RNA-seq revealed that loss of p63γ increases the expression of SCD1, a rate-limiting enzyme for synthesis of monounsaturated fatty acids, leading to altered lipid homeostasis. Together, our data indicate that TP63γ is the primary isoform of TP63 for tumor suppression but not development by maintaining normal inflammatory response and lipid homeostasis.https://doi.org/10.1038/s41420-025-02326-x |
| spellingShingle | Xinbin Chen Wenqiang Sun Xiangmudong Kong Xin Ming Yanhong Zhang Wensheng Yan Shakur Mohibi Mingyi Chen Keith Mitchell Jin Zhang TAp63γ is the primary isoform of TP63 for tumor suppression but not development Cell Death Discovery |
| title | TAp63γ is the primary isoform of TP63 for tumor suppression but not development |
| title_full | TAp63γ is the primary isoform of TP63 for tumor suppression but not development |
| title_fullStr | TAp63γ is the primary isoform of TP63 for tumor suppression but not development |
| title_full_unstemmed | TAp63γ is the primary isoform of TP63 for tumor suppression but not development |
| title_short | TAp63γ is the primary isoform of TP63 for tumor suppression but not development |
| title_sort | tap63γ is the primary isoform of tp63 for tumor suppression but not development |
| url | https://doi.org/10.1038/s41420-025-02326-x |
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