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Consequence of the tumor-associated conversion to cyclin D1b.

Augello MA, Berman-Booty LD, Carr R, Yoshida A, Dean JL, Schiewer MJ, Feng FY, Tomlins SA, Gao E, Koch WJ, Benovic JL, Diehl JA, Knudsen KE - EMBO Mol Med (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

No MeSH data available.


Related in: MedlinePlus

Model of cyclin D1b function in development and tumorigenesisTop: Comparison of the observed phenotypes noted in the Ccnd1KI/KI and Ccnd1−/− mice (Sicinski et al, 1995). Bottom: Summation of the pro-oncogenic phenotypes associated with cyclin D1b expression in cell-based models.
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fig08: Model of cyclin D1b function in development and tumorigenesisTop: Comparison of the observed phenotypes noted in the Ccnd1KI/KI and Ccnd1−/− mice (Sicinski et al, 1995). Bottom: Summation of the pro-oncogenic phenotypes associated with cyclin D1b expression in cell-based models.

Mentions: Here, a novel genetically engineered mouse model was used to convert cyclin D1a to cyclin D1b, allowing for first-in-field analysis of cyclin D1b in vivo and under control of the endogenous promoter (Fig1). Notably, cyclin D1b expression phenocopied only a selected subset of Ccnd1−/− mouse aberrations (Fig2), supporting the concept that cyclin D1b harbors distinct functions from that of cyclin D1a. Parallel studies utilizing isoform-specific models revealed the oncogenic potential of cyclin D1b, which further cooperated with known oncogenes to promote cellular transformation and tumor growth at high frequency (Figs3, 4 and 5), was associated with persistent DNA damage signals (Fig6). Furthermore, Ccnd1KI/KI cells were sensitized to cell cycle arrest and senescence though combined therapeutic intervention (Fig7), providing the first preclinical evidence of mechanisms to target cyclin D1b-expressing tumors. Collectively, this new model system unveiled novel functions of cyclin D1b in both development and tumorigenesis (Fig8) and identified means to target tumor cells that depend upon cyclin D1b expression.


Consequence of the tumor-associated conversion to cyclin D1b.

Augello MA, Berman-Booty LD, Carr R, Yoshida A, Dean JL, Schiewer MJ, Feng FY, Tomlins SA, Gao E, Koch WJ, Benovic JL, Diehl JA, Knudsen KE - EMBO Mol Med (2015)

Model of cyclin D1b function in development and tumorigenesisTop: Comparison of the observed phenotypes noted in the Ccnd1KI/KI and Ccnd1−/− mice (Sicinski et al, 1995). Bottom: Summation of the pro-oncogenic phenotypes associated with cyclin D1b expression in cell-based models.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492821&req=5

fig08: Model of cyclin D1b function in development and tumorigenesisTop: Comparison of the observed phenotypes noted in the Ccnd1KI/KI and Ccnd1−/− mice (Sicinski et al, 1995). Bottom: Summation of the pro-oncogenic phenotypes associated with cyclin D1b expression in cell-based models.
Mentions: Here, a novel genetically engineered mouse model was used to convert cyclin D1a to cyclin D1b, allowing for first-in-field analysis of cyclin D1b in vivo and under control of the endogenous promoter (Fig1). Notably, cyclin D1b expression phenocopied only a selected subset of Ccnd1−/− mouse aberrations (Fig2), supporting the concept that cyclin D1b harbors distinct functions from that of cyclin D1a. Parallel studies utilizing isoform-specific models revealed the oncogenic potential of cyclin D1b, which further cooperated with known oncogenes to promote cellular transformation and tumor growth at high frequency (Figs3, 4 and 5), was associated with persistent DNA damage signals (Fig6). Furthermore, Ccnd1KI/KI cells were sensitized to cell cycle arrest and senescence though combined therapeutic intervention (Fig7), providing the first preclinical evidence of mechanisms to target cyclin D1b-expressing tumors. Collectively, this new model system unveiled novel functions of cyclin D1b in both development and tumorigenesis (Fig8) and identified means to target tumor cells that depend upon cyclin D1b expression.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

No MeSH data available.


Related in: MedlinePlus