Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells
High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-H...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/3/489 |
| _version_ | 1797406818475966464 |
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| author | Claire D. James Siddharth Saini Fatmata Sesay Kevin Ko Jessica Felthousen-Rusbasan Audra N. Iness Tara Nulton Brad Windle Mikhail G. Dozmorov Iain M. Morgan Larisa Litovchick |
| author_facet | Claire D. James Siddharth Saini Fatmata Sesay Kevin Ko Jessica Felthousen-Rusbasan Audra N. Iness Tara Nulton Brad Windle Mikhail G. Dozmorov Iain M. Morgan Larisa Litovchick |
| author_sort | Claire D. James |
| collection | DOAJ |
| description | High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers. |
| first_indexed | 2024-03-09T03:32:07Z |
| format | Article |
| id | doaj.art-0c4b44ac554847768d75fc62c5fc80a7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T03:32:07Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0c4b44ac554847768d75fc62c5fc80a72023-12-03T14:53:53ZengMDPI AGCancers2072-66942021-01-0113348910.3390/cancers13030489Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human CellsClaire D. James0Siddharth Saini1Fatmata Sesay2Kevin Ko3Jessica Felthousen-Rusbasan4Audra N. Iness5Tara Nulton6Brad Windle7Mikhail G. Dozmorov8Iain M. Morgan9Larisa Litovchick10Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, VA 23298, USADepartment of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University (VCU), Richmond, VA 23298, USADepartment of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University (VCU), Richmond, VA 23298, USAPhilips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, VA 23298, USADepartment of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University (VCU), Richmond, VA 23298, USADepartment of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University (VCU), Richmond, VA 23298, USAPhilips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, VA 23298, USAPhilips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, VA 23298, USADepartment of Biostatistics, Virginia Commonwealth University (VCU), Richmond, VA 23298, USAPhilips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University (VCU), Richmond, VA 23298, USADepartment of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University (VCU), Richmond, VA 23298, USAHigh-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers.https://www.mdpi.com/2072-6694/13/3/489human papillomavirusoncogenic transformationtranscriptioncell cycleprotein complexhead and neck cancer |
| spellingShingle | Claire D. James Siddharth Saini Fatmata Sesay Kevin Ko Jessica Felthousen-Rusbasan Audra N. Iness Tara Nulton Brad Windle Mikhail G. Dozmorov Iain M. Morgan Larisa Litovchick Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells Cancers human papillomavirus oncogenic transformation transcription cell cycle protein complex head and neck cancer |
| title | Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells |
| title_full | Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells |
| title_fullStr | Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells |
| title_full_unstemmed | Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells |
| title_short | Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells |
| title_sort | restoring the dream complex inhibits the proliferation of high risk hpv positive human cells |
| topic | human papillomavirus oncogenic transformation transcription cell cycle protein complex head and neck cancer |
| url | https://www.mdpi.com/2072-6694/13/3/489 |
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