title: 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 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.
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Michael A
authors: MA
authors: Augello
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Lisa D
authors: LD
authors: Berman-Booty
authors: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Richard
authors: R
authors: Carr
authors: Medical University of South Carolina, Charleston, SC, USA Hollings Cancer Center, Charleston, SC, USA.
authors: Akihiro
authors: A
authors: Yoshida
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Jeffry L
authors: JL
authors: Dean
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Matthew J
authors: MJ
authors: Schiewer
authors: Michigan Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, USA Comprehensive Cancer Center University of Michigan Medical Center, Ann Arbor, MI, USA.
authors: Felix Y
authors: FY
authors: Feng
authors: Michigan Center for Translational Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA Comprehensive Cancer Center University of Michigan Medical Center, Ann Arbor, MI, USA Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors: Scott A
authors: SA
authors: Tomlins
authors: Pharmacology & Center for Translational Medicine, Philadelphia, PA, USA.
authors: Erhe
authors: E
authors: Gao
authors: Pharmacology & Center for Translational Medicine, Philadelphia, PA, USA Temple University School of Medicine, Philadelphia, PA, USA.
authors: Walter J
authors: WJ
authors: Koch
authors: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Jeffrey L
authors: JL
authors: Benovic
authors: Medical University of South Carolina, Charleston, SC, USA Hollings Cancer Center, Charleston, SC, USA.
authors: John Alan
authors: JA
authors: Diehl
authors: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA Department of Urology, Thomas Jefferson University, Philadelphia, PA, USA Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, USA karen.knudsen@jefferson.edu.
authors: Karen E
authors: KE
authors: Knudsen
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D019938:Cyclin D1
keywords: PARP; cell cycle; cyclin; cyclin D1b