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PMID:18483258

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Citation

He, YY, Council, SE, Feng, L and Chignell, CF (2008) UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes. Cancer Res. 68:3752-8

Abstract

UVA (315-400 nm), which constitutes approximately 95% of the UV irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. Here, we show that a low, nonlethal dose of UVA induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, whereas siRNA knockdown of cyclin D1 blocked the UVA-induced cell cycle progression, indicating that this process is mediated by cyclin D1. UVA irradiation also induced AKT activation; when cells were incubated with phosphatidylinositol-3-OH kinase/AKT inhibitor or infected with dominant-negative AKT, cyclin D1 up-regulation, cell cycle progression, and proliferation were inhibited, suggesting that AKT activation is required for UVA-induced cell cycle progression. In contrast, extracellular signal-regulated kinase (ERK) was not activated by UVA exposure; incubation with ERK/mitogen-activated protein kinase inhibitor had no effect on UVA-induced cyclin D1 up-regulation and cell cycle progression. Activation of epidermal growth factor receptor (EGFR) was observed after UVA exposure. EGFR kinase inhibitor AG attenuated the UVA-induced AKT/cyclin D1 pathway and cell cycle progression, indicating that EGFR is upstream of AKT/cyclin D1 pathway activation. Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of a disintegrin and metalloprotease (ADAM)17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. Identification of these signaling pathways in UVA-induced cell proliferation will facilitate the development of efficient and safe chemopreventive and therapeutic strategies for skin cancer.

Links

PubMed PMC2666770 Online version:10.1158/0008-5472.CAN-07-6138

Keywords

ADAM Proteins/metabolism; Antineoplastic Agents/pharmacology; Cell Cycle/drug effects; Cell Line, Tumor; Cell Proliferation; Cyclin D1/metabolism; Enzyme Inhibitors/pharmacology; Humans; Keratinocytes/metabolism; Models, Biological; Phosphatidylinositol 3-Kinases/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Receptor, Epidermal Growth Factor/metabolism; Skin Neoplasms/pathology; Ultraviolet Rays

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CCND1

involved_in

GO:0000082: G1/S transition of mitotic cell cycle

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCND1

involved_in

GO:0070141: response to UV-A

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA17

involved_in

GO:1900087: positive regulation of G1/S transition of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA17

involved_in

GO:0045741: positive regulation of epidermal growth factor-activated receptor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADA17

involved_in

GO:0045737: positive regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:1900087: positive regulation of G1/S transition of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0070141: response to UV-A

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AKT1

involved_in

GO:0045737: positive regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR_original

GO:0031659: positive regulation of cyclin-dependent protein kinase activity involved in G1/S

IDA: Inferred from Direct Assay: :

P


HUMAN:EGFR_original

GO:0070141: response to UV-A

IDA: Inferred from Direct Assay: :

P


HUMAN:EGFR_original

GO:0031659: positive regulation of cyclin-dependent protein kinase activity involved in G1/S

IDA: Inferred from Direct Assay:

P


HUMAN:EGFR_original

GO:0070141: response to UV-A

IDA: Inferred from Direct Assay:

P


HUMAN:EGFR

involved_in

GO:1900087: positive regulation of G1/S transition of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR

involved_in

GO:0070141: response to UV-A

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR

involved_in

GO:0045737: positive regulation of cyclin-dependent protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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