Erbb2 suppresses DNA damage-induced checkpoint activation and UV-induced mouse skin tumorigenesis.
The Erbb2 receptor is activated by UV irradiation, the primary cause of non-melanoma skin cancer. We hypothesized that Erbb2 activation contributes to UV-induced skin tumorigenesis by suppressing cell cycle arrest. Consistent with this hypothesis, inhibition of Erbb2 in v-ras(Ha) transgenic mice before UV exposure resulted in both 56% fewer skin tumors and tumors that were 70% smaller. Inhibition of the UV-induced activation of Erbb2 also resulted in milder epidermal hyperplasia, S-phase accumulation, and decreased levels of the cell cycle regulator Cdc25a, suggesting altered cell cycle regulation on inhibition of Erbb2. Further investigation using inhibition or genetic deletion of Erbb2 in vitro revealed reduced Cdc25a levels and increased S-phase arrest in UV-irradiated cells lacking Erbb2 activity. Ectopic expression of Cdc25a prevented UV-induced S-phase arrest in keratinocytes lacking Erbb2 activity, demonstrating that maintenance of Cdc25a by Erbb2 suppresses cell cycle arrest. Examination of checkpoint pathway activation upstream of Cdc25a revealed Erbb2 activation did not alter Ataxia Telangiectasia and Rad3-related/Ataxia Telangiectasia Mutated activity but increased inhibitory phosphorylation of Chk1-Ser(280). Since Akt phosphorylates Chk1-Ser(280), the effect of Erbb2 on phosphatidyl inositol-3-kinase (PI3K)/Akt signaling during UV-induced cell cycle arrest was determined. Erbb2 ablation reduced the UV-induced activation of PI3K while inhibition of PI3K/Akt increased UV-induced S-phase arrest. Thus, UV-induced Erbb2 activation increases skin tumorigenesis through inhibitory phosphorylation of Chk1, Cdc25a maintenance, and suppression of S-phase arrest via a PI3K/Akt-dependent mechanism.
Madson
Justin G
JG
Department of Biomedical Sciences, School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
Lynch
David T
DT
Svoboda
Jessica
J
Ophardt
Rebecca
R
Yanagida
Jodi
J
Putta
Sumanth K
SK
Bowles
Andrew
A
Trempus
Carol S
CS
Tennant
Raymond W
RW
Hansen
Laura A
LA
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000528:radiation effects; D018816:Genes, cdc / Q000528:radiation effects*; D015151:Immunoblotting; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000528:radiation effects; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000528:radiation effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D020687:cdc25 Phosphatases / Q000378:metabolism / Q000528:radiation effects
D000071877:Checkpoint Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020687:cdc25 Phosphatases; C524056:Erbb2 protein, mouse; C000605869:Chek1 protein, mouse; C517005:Cdc25a protein, mouse