Parkin (PK) is an E3-ligase harboring
tumor suppressor properties that has been associated to various
cancer types including
glioblastoma (GBM). However, PK is also a
transcription factor (TF), the contribution of which to GBM etiology remains to be established. Methods: The impact of PK on GBM cells proliferation was analyzed by real-time impedance measurement and flow cytometry.
Cyclins A and B
proteins, promoter activities and
mRNA levels were measured by western blot,
luciferase assay and quantitative real-time PCR.
Protein-
protein and
protein-promoter interactions were performed by co-immunoprecipitation and by ChIP approaches. The contribution of endogenous PK to
tumor progression in vivo was performed by allografts of GL261 GBM cells in wild-type and PK knockout mice. Results: We show that overexpressed and endogenous PK control GBM cells proliferation by modulating the S and G2/M phases of the cell cycle via the trans-repression of
cyclin A and
cyclin B genes. We establish that
cyclin B is regulated by both E3-ligase and TF PK functions while
cyclin A is exclusively regulated by PK TF function. PK invalidation leads to enhanced
tumor progression in immunocompetent mice suggesting an impact of PK-dependent
tumor environment to
tumor development. We show that PK is secreted by neuronal cells and recaptured by
tumor cells. Recaptured PK lowered
cyclins levels and decreased GBM cells proliferation. Further, PK expression is decreased in human GBM biopsies and its expression is inversely correlated to both
cyclins A and B expressions. Conclusion: Our work demonstrates that PK
tumor suppressor function contributes to the control of
tumor by its cellular environment. It also shows a key role of PK TF function in GBM development via the control of
cyclins in vitro and in vivo. It suggests that therapeutic strategies aimed at controlling PK shuttling to the nucleus may prove useful to treat GBM.