Consequence of the tumor‐associated conversion to cyclin D1b
Abstract Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncov...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2015-05-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201404242 |
| _version_ | 1797280670979981312 |
|---|---|
| author | Michael A Augello Lisa D Berman‐Booty Richard Carr 3rd Akihiro Yoshida Jeffry L Dean Matthew J Schiewer Felix Y Feng Scott A Tomlins Erhe Gao Walter J Koch Jeffrey L Benovic John Alan Diehl Karen E Knudsen |
| author_facet | Michael A Augello Lisa D Berman‐Booty Richard Carr 3rd Akihiro Yoshida Jeffry L Dean Matthew J Schiewer Felix Y Feng Scott A Tomlins Erhe Gao Walter J Koch Jeffrey L Benovic John Alan Diehl Karen E Knudsen |
| author_sort | Michael A Augello |
| collection | DOAJ |
| description | Abstract Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non‐redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b‐driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre‐clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant. |
| first_indexed | 2024-03-07T16:44:40Z |
| format | Article |
| id | doaj.art-c0a939ceeb9240749fd9c3c0d5d3e22e |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:44:40Z |
| publishDate | 2015-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-c0a939ceeb9240749fd9c3c0d5d3e22e2024-03-03T07:05:14ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-05-017562864710.15252/emmm.201404242Consequence of the tumor‐associated conversion to cyclin D1bMichael A Augello0Lisa D Berman‐Booty1Richard Carr 3rd2Akihiro Yoshida3Jeffry L Dean4Matthew J Schiewer5Felix Y Feng6Scott A Tomlins7Erhe Gao8Walter J Koch9Jeffrey L Benovic10John Alan Diehl11Karen E Knudsen12Department of Cancer Biology Thomas Jefferson University Philadelphia PA USADepartment of Cancer Biology Thomas Jefferson University Philadelphia PA USAKimmel Cancer Center Thomas Jefferson University Philadelphia PA USAMedical University of South Carolina Charleston SC USADepartment of Cancer Biology Thomas Jefferson University Philadelphia PA USADepartment of Cancer Biology Thomas Jefferson University Philadelphia PA USAMichigan Center for Translational Pathology University of Michigan Medical Center Ann Arbor MI USAMichigan Center for Translational Pathology University of Michigan Medical Center Ann Arbor MI USAPharmacology & Center for Translational Medicine Philadelphia PA USAPharmacology & Center for Translational Medicine Philadelphia PA USAKimmel Cancer Center Thomas Jefferson University Philadelphia PA USAMedical University of South Carolina Charleston SC USADepartment of Cancer Biology Thomas Jefferson University Philadelphia PA USAAbstract Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non‐redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote tumor growth in vivo. Further molecular interrogation uncovered unexpected links between cyclin D1b and the DNA damage/PARP1 regulatory networks, which could be exploited to suppress cyclin D1b‐driven tumors. Collectively, these data are the first to define the consequence of cyclin D1b expression on normal cellular function, present evidence for cyclin D1b as an oncogene, and provide pre‐clinical evidence of effective methods to thwart growth of cells dependent upon this oncogenic variant.https://doi.org/10.15252/emmm.201404242cell cyclecyclincyclin D1bPARP |
| spellingShingle | Michael A Augello Lisa D Berman‐Booty Richard Carr 3rd Akihiro Yoshida Jeffry L Dean Matthew J Schiewer Felix Y Feng Scott A Tomlins Erhe Gao Walter J Koch Jeffrey L Benovic John Alan Diehl Karen E Knudsen Consequence of the tumor‐associated conversion to cyclin D1b EMBO Molecular Medicine cell cycle cyclin cyclin D1b PARP |
| title | Consequence of the tumor‐associated conversion to cyclin D1b |
| title_full | Consequence of the tumor‐associated conversion to cyclin D1b |
| title_fullStr | Consequence of the tumor‐associated conversion to cyclin D1b |
| title_full_unstemmed | Consequence of the tumor‐associated conversion to cyclin D1b |
| title_short | Consequence of the tumor‐associated conversion to cyclin D1b |
| title_sort | consequence of the tumor associated conversion to cyclin d1b |
| topic | cell cycle cyclin cyclin D1b PARP |
| url | https://doi.org/10.15252/emmm.201404242 |
| work_keys_str_mv | AT michaelaaugello consequenceofthetumorassociatedconversiontocyclind1b AT lisadbermanbooty consequenceofthetumorassociatedconversiontocyclind1b AT richardcarr3rd consequenceofthetumorassociatedconversiontocyclind1b AT akihiroyoshida consequenceofthetumorassociatedconversiontocyclind1b AT jeffryldean consequenceofthetumorassociatedconversiontocyclind1b AT matthewjschiewer consequenceofthetumorassociatedconversiontocyclind1b AT felixyfeng consequenceofthetumorassociatedconversiontocyclind1b AT scottatomlins consequenceofthetumorassociatedconversiontocyclind1b AT erhegao consequenceofthetumorassociatedconversiontocyclind1b AT walterjkoch consequenceofthetumorassociatedconversiontocyclind1b AT jeffreylbenovic consequenceofthetumorassociatedconversiontocyclind1b AT johnalandiehl consequenceofthetumorassociatedconversiontocyclind1b AT kareneknudsen consequenceofthetumorassociatedconversiontocyclind1b |