TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response
The MiT/TFE family of transcription factors (MITF, TFE3, and TFEB), which control transcriptional programs for autophagy and lysosome biogenesis have emerged as regulators of energy metabolism in cancer. Thus, their activation increases lysosomal catabolic function to sustain cancer cell growth and...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/5/1186 |
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| author | Sandra Pisonero-Vaquero Chiara Soldati Marcella Cesana Andrea Ballabio Diego Luis Medina |
| author_facet | Sandra Pisonero-Vaquero Chiara Soldati Marcella Cesana Andrea Ballabio Diego Luis Medina |
| author_sort | Sandra Pisonero-Vaquero |
| collection | DOAJ |
| description | The MiT/TFE family of transcription factors (MITF, TFE3, and TFEB), which control transcriptional programs for autophagy and lysosome biogenesis have emerged as regulators of energy metabolism in cancer. Thus, their activation increases lysosomal catabolic function to sustain cancer cell growth and survival in stress conditions. Here, we found that TFEB depletion dramatically reduces basal expression levels of the cyclin-dependent kinase (CDK) inhibitor p21/WAF1 in various cell types. Conversely, TFEB overexpression increases p21 in a p53-dependent manner. Furthermore, induction of DNA damage using doxorubicin induces TFEB-mediated activation of p21, delays G2/M phase arrest, and promotes cell survival. Pharmacological inhibition of p21, instead, abrogates TFEB-mediated protection during the DNA damage response. Together, our findings uncover a novel and direct role of TFEB in the regulation of p21 expression in both steady-state conditions and during the induction of DNA-damage response (DDR). Our observations might open novel therapeutic strategies to promote cancer cell death by targeting the TFEB-p21 pathway in the presence of genotoxic agents. |
| first_indexed | 2024-03-10T19:55:40Z |
| format | Article |
| id | doaj.art-9177d5d42b5d4ad3bfa972399ed09ecc |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:55:40Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-9177d5d42b5d4ad3bfa972399ed09ecc2023-11-19T23:58:41ZengMDPI AGCells2073-44092020-05-0195118610.3390/cells9051186TFEB Modulates p21/WAF1/CIP1 during the DNA Damage ResponseSandra Pisonero-Vaquero0Chiara Soldati1Marcella Cesana2Andrea Ballabio3Diego Luis Medina4Telethon Institute of Genetics and Medicine (TIGEM), High Content Screening facility, Via Campi Flegrei 34, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine (TIGEM), High Content Screening facility, Via Campi Flegrei 34, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine (TIGEM), High Content Screening facility, Via Campi Flegrei 34, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine (TIGEM), High Content Screening facility, Via Campi Flegrei 34, 80078 Pozzuoli, ItalyTelethon Institute of Genetics and Medicine (TIGEM), High Content Screening facility, Via Campi Flegrei 34, 80078 Pozzuoli, ItalyThe MiT/TFE family of transcription factors (MITF, TFE3, and TFEB), which control transcriptional programs for autophagy and lysosome biogenesis have emerged as regulators of energy metabolism in cancer. Thus, their activation increases lysosomal catabolic function to sustain cancer cell growth and survival in stress conditions. Here, we found that TFEB depletion dramatically reduces basal expression levels of the cyclin-dependent kinase (CDK) inhibitor p21/WAF1 in various cell types. Conversely, TFEB overexpression increases p21 in a p53-dependent manner. Furthermore, induction of DNA damage using doxorubicin induces TFEB-mediated activation of p21, delays G2/M phase arrest, and promotes cell survival. Pharmacological inhibition of p21, instead, abrogates TFEB-mediated protection during the DNA damage response. Together, our findings uncover a novel and direct role of TFEB in the regulation of p21 expression in both steady-state conditions and during the induction of DNA-damage response (DDR). Our observations might open novel therapeutic strategies to promote cancer cell death by targeting the TFEB-p21 pathway in the presence of genotoxic agents.https://www.mdpi.com/2073-4409/9/5/1186TFEBp21DNA-damage responsecell cycleautophagycancer |
| spellingShingle | Sandra Pisonero-Vaquero Chiara Soldati Marcella Cesana Andrea Ballabio Diego Luis Medina TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response Cells TFEB p21 DNA-damage response cell cycle autophagy cancer |
| title | TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response |
| title_full | TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response |
| title_fullStr | TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response |
| title_full_unstemmed | TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response |
| title_short | TFEB Modulates p21/WAF1/CIP1 during the DNA Damage Response |
| title_sort | tfeb modulates p21 waf1 cip1 during the dna damage response |
| topic | TFEB p21 DNA-damage response cell cycle autophagy cancer |
| url | https://www.mdpi.com/2073-4409/9/5/1186 |
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