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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
UVB-induced G2 arrest of human melanocytes involves Cdc2 sequestration by Gadd45a in nuclear speckles
Caroline Fayolle1, Julie Pourchet, Aurélie Cohen
1INSERM U590, Oncogenèse et Progression Tumorale, Université Lyon1, Centre Léon Bérard, Lyon, France.
Abstract:
Exposure to solar UVB radiation is involved in the development of cutaneous melanoma. We previously showed that human melanocytes and melanoma cells respond to UVB radiation via a p53-independent pathway involving GADD45A activation. Here, we determined that UVB-induction of Gadd45a is necessary for G(2) arrest and that Gadd45a and its partner p21(Waf1) colocalize in nuclear bodies called Nuclear Speckles. We further observed that UVB-induced G(2) arrest is associated with Cdc2 accumulation in these Nuclear Speckles. Knock-down of Gadd45a expression by RNA interference prevents both UVB-induced Cdc2 accumulation in Nuclear Speckles and G(2) arrest. Our results demonstrate that UVB-induced G(2) arrest of melanoma cells is Gadd45a-dependent. Furthermore, we show that Cdc2 sequestration by Gadd45a occurs in Nuclear Speckles, suggesting a new role for these nuclear bodies, so far only linked to RNA maturation.
Insights
Solar UVB radiation triggers skin cancer. This study reveals that Gadd45a protein is essential for melanoma cell cycle arrest after UVB exposure, highlighting a new role for nuclear speckles.
Area of Science:
- Molecular Biology
- Dermatology
- Cancer Research
Background:
- Ultraviolet B (UVB) radiation is a known factor in cutaneous melanoma development.
- Previous research identified a p53-independent pathway involving GADD45A activation in response to UVB in melanocytes and melanoma cells.
Purpose of the Study:
- To investigate the role of Gadd45a in UVB-induced cell cycle arrest in melanoma cells.
- To elucidate the mechanism of Gadd45a involvement in G2 arrest and its interaction with other cell cycle regulators.
Main Methods:
- Utilized RNA interference to knock down Gadd45a expression in melanoma cells.
- Examined the effects of Gadd45a knockdown on UVB-induced G2 arrest and Cdc2 localization.
- Investigated the colocalization of Gadd45a and p21(Waf1) in nuclear structures.
Main Results:
- UVB-induced Gadd45a expression was found to be necessary for G2 cell cycle arrest.
- Gadd45a and p21(Waf1) were observed to colocalize within nuclear bodies known as Nuclear Speckles.
- UVB-induced G2 arrest correlated with the accumulation of Cdc2 within these Nuclear Speckles, a process dependent on Gadd45a.
Conclusions:
- UVB-induced G2 arrest in melanoma cells is dependent on Gadd45a.
- Cdc2 sequestration by Gadd45a within Nuclear Speckles represents a novel mechanism contributing to cell cycle arrest.
- Nuclear Speckles may play a previously unrecognized role in regulating cell cycle progression following DNA damage.
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