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.
Highlights
Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome
To develop robust genetic systems of cyclin D1b production under the endogenous promoter, a gene-targeting construct was generated wherein all C-terminal-encoding components of the murine Ccnd1 gene were replaced with the C-terminal sequences responsible for human cyclin D1b production
The use of human exon 4/intron 4 and removal of murine exon 5/30 UTR were necessary to both eliminate the possibility of full-length transcript a production, and to foster production of transcript b, encoding the unique C-terminus harbored by cyclin D1b
Summary
Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. Mutations within the coding region of cyclin D1, found in cases of esophageal and endometrial cancer (Moreno-Bueno et al, 2003; Benzeno et al, 2006), have yet to be associated with clinical markers of disease progression, together suggesting that the observed oncogenic functions of cyclin D1 involve additional mechanisms of deregulation Consistent with this concept, emerging clinical evidence suggests that alternative splicing of cyclin D1 transcript (cyclin D1a) to the shorter isoform cyclin D1b occurs frequently in human malignancy (Augello et al, 2014; Musgrove et al, 2011; Wang et al, 2008; Comstock et al, 2009), and appears to be a major mechanism though which cyclin D1 exerts its oncogenic activity. This study established a first-in-field model of the switch to cyclin D1b, identified unique roles for this isoform, and put forth novel strategies for treating cyclin D1b-positive tumors
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