γ-Irradiation–Induced DNA Damage Checkpoint Activation Involves Feedback Regulation between Extracellular Signal-Regulated Kinase 1/2 and BRCA1

Abstract

Previous studies from our laboratory have shown that the activation of G2-M checkpoint after exposure of MCF-7 breast cancer cells to γ-irradiation (IR) is dependent on the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Studies presented in this report indicate that IR exposure of MCF-7 cells is associated with a marked increase in expression of breast cancer 1 (BRCA1) tumor suppressor, an effect that requires ERK1/2 activation and involves posttranscriptional control mechanisms. Furthermore, reciprocal coimmunoprecipitation, as well as colocalization studies, indicate an interaction between BRCA1 and ERK1/2 in both nonirradiated and irradiated cells. Studies using short hairpin RNA targeting BRCA1 show that BRCA1 expression is necessary for IR-induced G2-M cell cycle arrest, as well as ERK1/2 activation in MCF-7 cells. Although BRCA1 expression is not required for IR-induced phosphorylation of ataxia telangiectasia mutated (ATM)–Ser1981, it is required for ATM-mediated downstream signaling events, including IR-induced phosphorylation of Chk2-Thr68 and p53-Ser20. Moreover, BRCA1 expression is also required for IR-induced ATM and rad3 related activation and Chk1 phosphorylation in MCF-7 cells. These results implicate an important interaction between BRCA1 and ERK1/2 in the regulation of cellular response after IR-induced DNA damage in MCF-7 cells.

Loss of DUSP3 activity radiosensitizes human tumor cell lines via attenuation of DNA repair pathways

“…In this study, the activation of MAPK by stress-inducing agents promoted an increased level of phosphorylated H2AX, a marker of DNA damage caused by double-strand breaks [54], as demonstrated previously in other cellular systems [19][20][21][22]55,56]. actions as sensors of DNA strand break sites [57].…”

Mangiferin induces cell cycle arrest at G2/M phase through ATR-Chk1 pathway in HL-60 leukemia cells

“…Studies have found that Akt is hyperactivated in many human cancers, as it promotes proliferation and cancer cell survival in response to DNA-damaging agents (Fraser et al, 2011). In addition, the extracellular signal-regulated kinase 1/2 (ERK1/2) is also involved in ATM/ATR-mediated G2/M checkpoint activation (Yan et al, 2007(Yan et al, , 2008. It was found that 160 mM mangiferin dramatically inhibited phospho-Akt and phospho-ERK1/2 as well as total Akt protein in a time-dependent manner; total ERK1/2 protein level was slightly reduced as well after treatment at all time points ( Figure 4K and M).…”

Peroxiredoxin II Restrains DNA Damage-induced Death in Cancer Cells by Positively Regulating JNK-dependent DNA Repair

“…In the case of other stresses, such as hydroxyurea and ionizing radiation, ERK activation was required for S phase and G 2 /M checkpoint arrest, respectively (48,49). Moreover, Yan et al reported that ionizing radiation-induced ERK1/2 activation required a direct interaction with BRCA1 for G 2 /M cell cycle checkpoint arrest (50). Thus, the evidence suggests that ERK activation by DNA damage may preferentially be involved in cell cycle arrest before cell death.…”