Androgen dependent regulation of protein kinase A subunits in prostate cancer cells

Kvissel, Anne-Katrine; Ramberg, Håkon; Eide, T. J.; Svindland, Aud; Skålhegg, Bjørn Steen; Taskén, Kristin Austlid

doi:10.1016/j.cellsig.2006.07.011

Cited by 33 publications

(22 citation statements)

References 33 publications

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“…PKAC␤ protects MYC from proteasomal degradation, but does not repress MYC transcriptionally. This is consistent with the higher expression of PKAC␤ subunits in rapidly proliferating, MYC-overexpressing prostate cancer cells (31)(32)(33). Thus, through differential substrate selectivity, PKA catalytic isoforms regulate MYC differentially.…”

Section: Discussionsupporting

confidence: 68%

Protein Kinase A Regulates MYC Protein through Transcriptional and Post-translational Mechanisms in a Catalytic Subunit Isoform-specific Manner

Padmanabhan

Bieberich

2013

Journal of Biological Chemistry

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Background: MYC is rapidly degraded in cells, and its accumulation is associated with many human malignancies. Results: Sequential phosphorylation of MYC by protein kinase A (PKA) and polo-like kinase 1 (PLK1) protects MYC from proteasome-mediated degradation. Conclusion: A MYC-PKA-PLK1 signaling loop exists in cells. Significance: We highlight the importance of considering possible regulatory feedback loops while targeting molecules occupying hub positions in signaling pathways.

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Section: Discussionsupporting

confidence: 68%

Protein Kinase A Regulates MYC Protein through Transcriptional and Post-translational Mechanisms in a Catalytic Subunit Isoform-specific Manner

Padmanabhan

Bieberich

2013

Journal of Biological Chemistry

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“…Similar with previous reports (40,41), trenbolone increased the androgen receptor expression at both protein and mRNA levels. However, blocking androgen receptor did not abolish the enhancement of androgen receptor expression by trenbolone, suggesting non-androgen receptor-mediated effects exist (42,43). …”

Section: Discussionmentioning

confidence: 97%

Trenbolone enhances myogenic differentiation by enhancing β-catenin signaling in muscle-derived stem cells of cattle

Zhao¹,

Hu²,

Zhu³

et al. 2011

Domestic Animal Endocrinology

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Testosterone is a key hormone regulating animal growth and development, which promotes skeletal muscle growth and inhibits fat deposition; however the underlying mechanisms remain poorly defined. Because canonical Wingless and Int (Wnt)/β-catenin signaling promotes myogenesis, we hypothesized that testosterone regulates myogenesis through enhancing the β-catenin signaling pathway and the expression of its targeted genes. Muscle-derived stem cells were prepared from the skeletal muscle of fetal calf at day 180 of gestation, and treated with or without trenbolone (10 nM), a synthetic analog of testosterone, in a myogenic medium. Trenbolone treatment increased the protein levels of MyoD and myosin heavy chain, as well as the androgen receptor content. The myogenic effect of trenbolone was blocked by cyproterone acetate, a specific inhibitor of androgen receptor, showing that the myogenic effect of trenbolone was mediated by the androgen receptor. Immunoprecipitation (IP) showed that androgen receptor and β-catenin formed a complex, which was increased by trenbolone treatment. Trenbolone activated AMP-activated protein kinase, which might phosphorylate β-catenin at Ser 552, stabilizing β-catenin. Indeed, both cytoplasmic and nuclear β-catenin levels were increased following trenbolone treatment. As a result, β-catenin mediated transcriptional activity was enhanced by trenbolone treatment. In conclusion, these data provide evidences that testosterone increases cellular β-catenin content which promotes the expression of β-catenin targeted genes and myogenesis in the muscle-derived stem cells of cattle.

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“…It has been reported that differential G s -coupled GPCR signalling, PKA catalytic subunit switching and adenylyl cyclase isoform expression are observed between the androgen-sensitive (AS) and AI cancer phenotypes (Kasbohm et al , 2005; Kvissel et al , 2007; Flacke et al , 2013), implying that alterations in the regulation of cAMP signalling cascades are an important factor in prostate cancer progression (Merkle and Hoffmann, 2011). The actions of the ubiquitous second messenger cAMP are governed by the processes of spatially distinct synthesis and degradation where adenylyl cyclases mediate the synthesis of cAMP, and cyclic nucleotide phosphodiesterases (PDEs) represent the only known means by which cAMP is degraded in cells (Houslay, 2010).…”

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confidence: 99%

The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells

et al. 2014

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Background:Isoforms of the PDE4 family of cAMP-specific phosphodiesterases (PDEs) are expressed in a cell type-dependent manner and contribute to underpinning the paradigm of intracellular cAMP signal compartmentalisation. Here we identify the differential regulation of the PDE4D7 isoform during prostate cancer progression and uncover a role in controlling prostate cancer cell proliferation.Methods:PDE4 transcripts from 19 prostate cancer cell lines and xenografts were quantified by qPCR. PDE4D7 expression was further investigated because of its significant downregulation between androgen-sensitive (AS) and androgen-insensitive (AI) samples. Western blot analysis, PDE activity assay, immunofluorescent staining and cAMP responsive FRET assays were used to investigate the sub-plasma membrane localisation of a population of PDE4D7 in VCaP (AS) and PC3 (AI) cell lines. Disruption of this localisation pattern using dominant-negative protein expression and siRNA knockdown showed that PDE4D7 acts in opposition to proliferative signalling as assessed by electrical impedance-based proliferation assays.Results:Here we identify the differential regulation of the PDE4D7 isoform during prostate cancer progression. PDE4D7 is highly expressed in AS cells and starkly downregulated in AI samples. The significance of this downregulation is underscored by our finding that PDE4D7 contributes a major fraction of cAMP degrading PDE activity tethered at the plasma membrane and that displacement of PDE4D7 from this compartment leads to an increase in the proliferation of prostate cancer cells. PDE4D7 mRNA expression is not, however, directly regulated by the androgen receptor signalling axis despite an overlapping genomic structure with the androgen responsive gene PART1. PDE4D7, which locates to the plasma membrane, acts to supress aberrant non-steroidal growth signals within the prostate or AS metastasis.Conclusions:PDE4D7 expression is significantly downregulated between AS and AI cell phenotypes. This change in expression potentially provides a novel androgen-independent biomarker and manipulation of its activity or its expression may provide therapeutic possibilities and insights into contributory aspects of the complex molecular pathology of prostate cancer.

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Androgen dependent regulation of protein kinase A subunits in prostate cancer cells

Cited by 33 publications

References 33 publications

Protein Kinase A Regulates MYC Protein through Transcriptional and Post-translational Mechanisms in a Catalytic Subunit Isoform-specific Manner

Protein Kinase A Regulates MYC Protein through Transcriptional and Post-translational Mechanisms in a Catalytic Subunit Isoform-specific Manner

Trenbolone enhances myogenic differentiation by enhancing β-catenin signaling in muscle-derived stem cells of cattle

The cAMP phosphodiesterase-4D7 (PDE4D7) is downregulated in androgen-independent prostate cancer cells and mediates proliferation by compartmentalising cAMP at the plasma membrane of VCaP prostate cancer cells

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