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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

Cyclin D1b selectively rescues Ccnd1−/− phenotypesNeonates from 2 independent litters of Ccnd1+/KI × Ccnd1+/KI crosses were sacrificed at birth and genotyped. Mice were organized by genotype and total size measured.Mass of neonates was calculated at birth and average mass quantified (n = at least 4 mice per group).Mice were weighed weekly, and growth is plotted as the average mass of each genotype/week (left: male, right: female, n > 5 per gender and genotype).Mice were held by the tails and analyzed for the leg clasping phenotype. Representative images of Ccnd1+/+ and Ccnd1KI/KI age-matched mice are shown (n > 10 for each group).Top: Individual whole-cell lysates were generated from the eyes of mice of each genotype and analyzed for expression of +/+ cyclin D1 (cyclin D1a) and KI/KI cyclin D1b via immunoblot using antisera specific to each isoform. Bottom: Representative H&E staining of retinal tissue from Ccnd1+/+ and Ccnd1KI/KI mice showing individual layers of the retina. The ganglion cell layer and inner plexiform layer (G + IPL), inner nuclear layer (INL), and outer nuclear layer (ONL) were quantified (right). Images were taken at 400× magnification.Comparison of the phenotypes described in the Ccnd1−/− mouse with those observed in the Ccnd1KI/KI mouse, previously described (Sicinski et al, 1995).Data information: n = at least 4 for each genotype. Error bars represent the standard error of the mean (SEM), and significance was determined using a two-tailed Student's t-test.
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fig02: Cyclin D1b selectively rescues Ccnd1−/− phenotypesNeonates from 2 independent litters of Ccnd1+/KI × Ccnd1+/KI crosses were sacrificed at birth and genotyped. Mice were organized by genotype and total size measured.Mass of neonates was calculated at birth and average mass quantified (n = at least 4 mice per group).Mice were weighed weekly, and growth is plotted as the average mass of each genotype/week (left: male, right: female, n > 5 per gender and genotype).Mice were held by the tails and analyzed for the leg clasping phenotype. Representative images of Ccnd1+/+ and Ccnd1KI/KI age-matched mice are shown (n > 10 for each group).Top: Individual whole-cell lysates were generated from the eyes of mice of each genotype and analyzed for expression of +/+ cyclin D1 (cyclin D1a) and KI/KI cyclin D1b via immunoblot using antisera specific to each isoform. Bottom: Representative H&E staining of retinal tissue from Ccnd1+/+ and Ccnd1KI/KI mice showing individual layers of the retina. The ganglion cell layer and inner plexiform layer (G + IPL), inner nuclear layer (INL), and outer nuclear layer (ONL) were quantified (right). Images were taken at 400× magnification.Comparison of the phenotypes described in the Ccnd1−/− mouse with those observed in the Ccnd1KI/KI mouse, previously described (Sicinski et al, 1995).Data information: n = at least 4 for each genotype. Error bars represent the standard error of the mean (SEM), and significance was determined using a two-tailed Student's t-test.

Mentions: While several murine models have been characterized which mutate and/or toggle cyclin D1 expression, to date no genetic systems had been generated which assess cyclin D1b function under the endogenous promoter in vivo. Crosses between Ccnd1+/KI mice (> 20 mating pairs across multiple generations) revealed that Ccnd1KI/KI mice are born in typical Mendelian ratios (Supplementary Fig S1A), suggesting that cyclin D1b expression does not result in embryonic lethality. At birth, Ccnd1KI/KI pups were indistinguishable from wild-type littermates, as noted by virtually identical size (Fig2A) and mass (Fig2B). However, by 3 weeks of age, a significant reduction in size and weight was noted in the Ccnd1KI/KI mice, which persisted over a period of 8 weeks and was independent of gender (Fig2C). Further analysis of individual organ weight (adjusted for total body mass) revealed no significant difference between Ccnd1+/+, Ccnd1+/KI, or Ccnd1KI/KI animals, suggesting that diminished organ size was not causative for the observed reduction in mass. Notably, the growth rate of all animals was similar between 3 and 8 weeks of age, indicating that the reduction in size and mass occurs early in post-natal development. Interestingly, previous work modeling cyclin D1 loss (Ccnd1−/−) in an identical genetic background found a similar growth phenotype during early development, which persisted throughout the lifetime of Ccnd1−/− animals (Sicinski et al, 1995). Given the similarity between these two models, these data support the concept that cyclin D1b induction is not sufficient to restore the growth retardation phenotype observed in Ccnd1−/− mice and highlights the functional differences between the two cyclin D1 isoforms.


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)

Cyclin D1b selectively rescues Ccnd1−/− phenotypesNeonates from 2 independent litters of Ccnd1+/KI × Ccnd1+/KI crosses were sacrificed at birth and genotyped. Mice were organized by genotype and total size measured.Mass of neonates was calculated at birth and average mass quantified (n = at least 4 mice per group).Mice were weighed weekly, and growth is plotted as the average mass of each genotype/week (left: male, right: female, n > 5 per gender and genotype).Mice were held by the tails and analyzed for the leg clasping phenotype. Representative images of Ccnd1+/+ and Ccnd1KI/KI age-matched mice are shown (n > 10 for each group).Top: Individual whole-cell lysates were generated from the eyes of mice of each genotype and analyzed for expression of +/+ cyclin D1 (cyclin D1a) and KI/KI cyclin D1b via immunoblot using antisera specific to each isoform. Bottom: Representative H&E staining of retinal tissue from Ccnd1+/+ and Ccnd1KI/KI mice showing individual layers of the retina. The ganglion cell layer and inner plexiform layer (G + IPL), inner nuclear layer (INL), and outer nuclear layer (ONL) were quantified (right). Images were taken at 400× magnification.Comparison of the phenotypes described in the Ccnd1−/− mouse with those observed in the Ccnd1KI/KI mouse, previously described (Sicinski et al, 1995).Data information: n = at least 4 for each genotype. Error bars represent the standard error of the mean (SEM), and significance was determined using a two-tailed Student's t-test.
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Related In: Results  -  Collection

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fig02: Cyclin D1b selectively rescues Ccnd1−/− phenotypesNeonates from 2 independent litters of Ccnd1+/KI × Ccnd1+/KI crosses were sacrificed at birth and genotyped. Mice were organized by genotype and total size measured.Mass of neonates was calculated at birth and average mass quantified (n = at least 4 mice per group).Mice were weighed weekly, and growth is plotted as the average mass of each genotype/week (left: male, right: female, n > 5 per gender and genotype).Mice were held by the tails and analyzed for the leg clasping phenotype. Representative images of Ccnd1+/+ and Ccnd1KI/KI age-matched mice are shown (n > 10 for each group).Top: Individual whole-cell lysates were generated from the eyes of mice of each genotype and analyzed for expression of +/+ cyclin D1 (cyclin D1a) and KI/KI cyclin D1b via immunoblot using antisera specific to each isoform. Bottom: Representative H&E staining of retinal tissue from Ccnd1+/+ and Ccnd1KI/KI mice showing individual layers of the retina. The ganglion cell layer and inner plexiform layer (G + IPL), inner nuclear layer (INL), and outer nuclear layer (ONL) were quantified (right). Images were taken at 400× magnification.Comparison of the phenotypes described in the Ccnd1−/− mouse with those observed in the Ccnd1KI/KI mouse, previously described (Sicinski et al, 1995).Data information: n = at least 4 for each genotype. Error bars represent the standard error of the mean (SEM), and significance was determined using a two-tailed Student's t-test.
Mentions: While several murine models have been characterized which mutate and/or toggle cyclin D1 expression, to date no genetic systems had been generated which assess cyclin D1b function under the endogenous promoter in vivo. Crosses between Ccnd1+/KI mice (> 20 mating pairs across multiple generations) revealed that Ccnd1KI/KI mice are born in typical Mendelian ratios (Supplementary Fig S1A), suggesting that cyclin D1b expression does not result in embryonic lethality. At birth, Ccnd1KI/KI pups were indistinguishable from wild-type littermates, as noted by virtually identical size (Fig2A) and mass (Fig2B). However, by 3 weeks of age, a significant reduction in size and weight was noted in the Ccnd1KI/KI mice, which persisted over a period of 8 weeks and was independent of gender (Fig2C). Further analysis of individual organ weight (adjusted for total body mass) revealed no significant difference between Ccnd1+/+, Ccnd1+/KI, or Ccnd1KI/KI animals, suggesting that diminished organ size was not causative for the observed reduction in mass. Notably, the growth rate of all animals was similar between 3 and 8 weeks of age, indicating that the reduction in size and mass occurs early in post-natal development. Interestingly, previous work modeling cyclin D1 loss (Ccnd1−/−) in an identical genetic background found a similar growth phenotype during early development, which persisted throughout the lifetime of Ccnd1−/− animals (Sicinski et al, 1995). Given the similarity between these two models, these data support the concept that cyclin D1b induction is not sufficient to restore the growth retardation phenotype observed in Ccnd1−/− mice and highlights the functional differences between the two cyclin D1 isoforms.

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