ATR-dependent Activation of p38 MAP Kinase Is Responsible for Apoptotic Cell Death in Cells Depleted of Cdc7

Abstract

Cdc7 is a serine/threonine kinase that plays essential roles in the initiation of eukaryotic DNA replication and checkpoint response. In previous studies, depletion of Cdc7 by small interfering RNA was shown to induce an abortive S phase that led to the cell cycle arrest in normal human fibroblasts and apoptotic cell death in various cancer cells. Here we report that stressactivated p38 MAP kinase was activated and responsible for apoptotic cell death in Cdc7-depleted HeLa cells. The activation of p38 MAP kinase in the Cdc7-depleted cells was shown to depend on ATR, a major sensor kinase for checkpoint or DNA damage responses. Only the p38 MAP kinase, and not the other stress-activated kinases such as JNK or ERK, was activated, and both caspase 8 and caspase 9 were activated for the induction of apoptosis. Activation of apoptosis in Cdc7-depleted cells was completely abolished in cells treated with small interfering RNA or an inhibitor of the p38 MAP kinase, suggesting that p38 MAP kinase activation was responsible for apoptotic cell death. Taken together, we suggest that the ATR-dependent activation of the p38 MAP kinase is a major signaling pathway that induces apoptotic cell death after depletion of Cdc7 in cancer cells.

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

“…In addition, our data also indicate that the activation of p38MAPK can be mediated through both ATM and ATR. This information is extremely important, because activation of p38MAPK by g-radiation is an event that seems to be dependent on ATM (Lafarga et al, 2009), whereas in other situations such as CDC7 depletion, activation of p38MAPK appears to be dependent on ATR (Im and Lee, 2008). Our data clearly demonstrate that both proteins can be activated by 5-FU and are able to activate similar downstream signals, including p53 and p38MAPK.…”

The cell cycle and cancer

“…First-in-class Cdc7 inhibitors have broad tumour spectrum activity in preclinical models, consistent with loss of the protective checkpoint mechanism in most tumour types. Apoptotic cancer cell death in response to Cdc7 inhibition is p53-independent and, at least in some cancer cell lines, is mediated via the stress-activated protein p38MAPK in an ATM-and Rad3-related (ATR)-dependent manner [132]. Interestingly, in addition to its function in origin firing, Cdc7 kinase has been shown to play an essential role in mediating the ATR-Chk1 pathway by phosphorylating the Chk1 activator Claspin [133,134].…”

BMI-1 is important in bufalin-induced apoptosis of K562 cells

“…Knockdown of Cdc7 has been demonstrated to cause the death of cancer cells, but not normal cells, via p53-dependent pathways which are able to arrest the cell cycle, presumably in the G 1 phase (55,56). It has also been reported that Cdc7 knockdown induced p38-dependent cell death in HeLa cells (57). Cdc7 depletion is able to induce DNA damage in cancer cells (58), and activated Chk2 is capable of stabilizing the FoxM1 transcription factor, which induces the expression of cyclin B1 (59).…”