Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network
Myc, a member of the “Myc Network” of bHLH-ZIP transcription factors, supervises proliferation, metabolism, and translation. It also engages in crosstalk with the related “Mlx Network” to co-regulate overlapping genes and functions. We investigated the consequences of stepwise conditional inactivati...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/24/4087 |
| _version_ | 1797460954227671040 |
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| author | Huabo Wang Taylor Stevens Jie Lu Merlin Airik Rannar Airik Edward V. Prochownik |
| author_facet | Huabo Wang Taylor Stevens Jie Lu Merlin Airik Rannar Airik Edward V. Prochownik |
| author_sort | Huabo Wang |
| collection | DOAJ |
| description | Myc, a member of the “Myc Network” of bHLH-ZIP transcription factors, supervises proliferation, metabolism, and translation. It also engages in crosstalk with the related “Mlx Network” to co-regulate overlapping genes and functions. We investigated the consequences of stepwise conditional inactivation of Myc and Mlx in primary and SV40 T-antigen-immortalized murine embryonic fibroblasts (MEFs). <i>Myc</i>-knockout (<i>Myc</i>KO) and <i>Myc</i> × <i>Mlx</i> “double KO” (DKO)—but not <i>Mlx</i>KO—primary MEFs showed rapid growth arrest and displayed features of accelerated aging and senescence. However, DKO MEFs soon resumed proliferating, indicating that durable growth arrest requires an intact Mlx network. All three KO MEF groups deregulated multiple genes and functions pertaining to aging, senescence, and DNA damage recognition/repair. Immortalized KO MEFs proliferated in Myc’s absence while demonstrating variable degrees of widespread genomic instability and sensitivity to genotoxic agents. Finally, compared to primary <i>Myc</i>KO MEFs, DKO MEFs selectively downregulated numerous gene sets associated with the p53 and retinoblastoma (Rb) pathways and G<sub>2</sub>/M arrest. Thus, the reversal of primary <i>Myc</i>KO MEF growth arrest by either Mlx loss or SV40 T-antigen immortalization appears to involve inactivation of the p53 and/or Rb pathways. |
| first_indexed | 2024-03-09T17:12:31Z |
| format | Article |
| id | doaj.art-8f73e5a6de2c4fc8906e9b2509c3f992 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T17:12:31Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-8f73e5a6de2c4fc8906e9b2509c3f9922023-11-24T13:55:37ZengMDPI AGCells2073-44092022-12-011124408710.3390/cells11244087Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc NetworkHuabo Wang0Taylor Stevens1Jie Lu2Merlin Airik3Rannar Airik4Edward V. Prochownik5Division of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USADivision of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USADivision of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USADivision of Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USADivision of Nephrology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USADivision of Hematology/Oncology, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USAMyc, a member of the “Myc Network” of bHLH-ZIP transcription factors, supervises proliferation, metabolism, and translation. It also engages in crosstalk with the related “Mlx Network” to co-regulate overlapping genes and functions. We investigated the consequences of stepwise conditional inactivation of Myc and Mlx in primary and SV40 T-antigen-immortalized murine embryonic fibroblasts (MEFs). <i>Myc</i>-knockout (<i>Myc</i>KO) and <i>Myc</i> × <i>Mlx</i> “double KO” (DKO)—but not <i>Mlx</i>KO—primary MEFs showed rapid growth arrest and displayed features of accelerated aging and senescence. However, DKO MEFs soon resumed proliferating, indicating that durable growth arrest requires an intact Mlx network. All three KO MEF groups deregulated multiple genes and functions pertaining to aging, senescence, and DNA damage recognition/repair. Immortalized KO MEFs proliferated in Myc’s absence while demonstrating variable degrees of widespread genomic instability and sensitivity to genotoxic agents. Finally, compared to primary <i>Myc</i>KO MEFs, DKO MEFs selectively downregulated numerous gene sets associated with the p53 and retinoblastoma (Rb) pathways and G<sub>2</sub>/M arrest. Thus, the reversal of primary <i>Myc</i>KO MEF growth arrest by either Mlx loss or SV40 T-antigen immortalization appears to involve inactivation of the p53 and/or Rb pathways.https://www.mdpi.com/2073-4409/11/24/4087agingChREBPDNA repairMgaMondoAMnt |
| spellingShingle | Huabo Wang Taylor Stevens Jie Lu Merlin Airik Rannar Airik Edward V. Prochownik Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network Cells aging ChREBP DNA repair Mga MondoA Mnt |
| title | Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network |
| title_full | Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network |
| title_fullStr | Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network |
| title_full_unstemmed | Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network |
| title_short | Disruption of Multiple Overlapping Functions Following Stepwise Inactivation of the Extended Myc Network |
| title_sort | disruption of multiple overlapping functions following stepwise inactivation of the extended myc network |
| topic | aging ChREBP DNA repair Mga MondoA Mnt |
| url | https://www.mdpi.com/2073-4409/11/24/4087 |
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