The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses.

SUMMARY Resolved ER stress response is essential for intracellular homeostatic balance, but unsettled ER stress can lead to apoptosis. Here, we show that a pro-apoptotic p53 target, CDIP1, acts as a key signal transducer of ER stress-mediated apoptosis. We identify BAP31, B-cell receptor-associated protein 31, as an interacting partner of CDIP1. Upon ER stress, CDIP1 is induced and enhances an association with BAP31 at the ER membrane. We also show that CDIP1 binding to BAP31 is required for BAP31 cleavage upon ER stress and for BAP31-Bcl-2 association. The recruitment of Bcl-2 to the BAP31-CDIP1 complex, as well as CDIP1-dependent tBid and caspase-8 activation, contributes to BAX oligomerization. Genetic knockout of CDIP1 in mice leads to impaired response to ER stress-mediated apoptosis. Together, our data demonstrate that the CDIP1/BAP31-mediated regulation of mitochondrial apoptosis pathway represents a novel mechanism for establishing an ER-mitochondrial cross-talk for ER stress-mediated apoptosis signaling.

Among several chemotherapeutic agents, 5-fluorouracil (5-FU) has been widely used as a key drug in adjuvant chemotherapy for gastric cancer. However, no reliable marker, which predicts the response to 5-FU in an adjuvant setting, has been identified. Hypoxia-induced drug resistance, via upregulation of HIF-1a, is a major obstacle in the development of effective cancer therapy. However, few clinical studies have so far assessed the relationship between the HIF-1a expression and the chemo-resistance of gastric cancer patients in an adjuvant setting. We established 2 HIF-1a knockdown gastric cancer cell lines in order to clarify the role of HIF-1a in chemo-resistance against 5-FU. Furthermore, expression of HIF-1a was immunohistochemically assessed in 91 resected specimens. Sixty-four of 91 patients received 5-FU adjuvant chemotherapy after surgery. HIF-1a expression was associated with the significantly shorter relapse-free survival and disease-specific survival in the 64 patients of adjuvant group (p 5 0.026, 0.014, respectively), but not in the 27 of surgery group. Multivariate analysis showed that HIF-1a was an independent risk factor for relapse in 64 patients in the adjuvant group (p 5 0.029). In conclusion, the current study confirmed, for the first time that HIF-1a expression is an independent risk factor for relapse in high-risk gastric cancer patients who underwent curative surgery followed by adjuvant 5-FU chemotherapy. A favorable effect of 5-FU might therefore be expected in patients that do not express HIF-1a, whereas, other types of chemotherapy or additional treatments, such as HIF-1a inhibitors, should be considered in patients that do express HIF-1a.Despite its declining incidence, gastric cancer remains a worldwide health problem that is the fourth most common cancer and the second most frequent cause of cancer-related deaths. 1 Although curative surgery is essential in the treatment of gastric cancer, this single modality treatment seems to have reached its maximal achievable effect for local control and survival. 2 Various regimens of adjuvant chemotherapy, either with or without radiotherapy, have therefore been administered in the hope of preventing a disease relapse and improving the survival rate. [3][4][5] One early meta-analysis concluded that adjuvant chemotherapy did not improve survival, 6 whereas in the last decade, several meta-analyses have confirmed that adjuvant chemotherapy led to statistically significant reductions in mortality and the rate of relapse in comparison to surgery alone. 7-13 However, a consensus regarding a standard regimen has not been obtained among the world.Many drug combinations that include 5-fluorouracil (5-FU), platinum compounds, anthracyclines, taxanes and/or irinotecan have demonstrated promising activity in advanced gastric cancer. Among these chemotherapeutic agents, 5-FU has been widely used as a key drug in adjuvant chemotherapy. Thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are important enzymes in...