Heat shock protein 70-mediated sensitization of cells to apoptosis by Carboxyl-Terminal Modulator Protein

<p>Abstract</p> <p>Background</p> <p>The serine/threonine protein kinase B (PKB/Akt) is involved in insulin signaling, cellular survival, and transformation. Carboxyl-terminal modulator protein (CTMP) has been identified as a novel PKB binding partner in a yeast two-hybrid screen, and appears to be a negative PKB regulator with tumor suppressor-like properties. In the present study we investigate novel mechanisms by which CTMP plays a role in apoptosis process.</p> <p>Results</p> <p>CTMP is localized to mitochondria. Furthermore, CTMP becomes phosphorylated following the treatment of cells with pervanadate, an insulin-mimetic. Two serine residues (Ser37 and Ser38) were identified as novel <it>in vivo </it>phosphorylation sites of CTMP. Association of CTMP and heat shock protein 70 (Hsp70) inhibits the formation of complexes containing apoptotic protease activating factor 1 and Hsp70. Overexpression of CTMP increased the sensitivity of cells to apoptosis, most likely due to the inhibition of Hsp70 function.</p> <p>Conclusion</p> <p>Our data suggest that phosphorylation on Ser37/Ser38 of CTMP is important for the prevention of mitochondrial localization of CTMP, eventually leading to cell death by binding to Hsp70. In addition to its role in PKB inhibition, CTMP may therefore play a key role in mitochondria-mediated apoptosis by localizing to mitochondria.</p

Combustion and Emission Characteristics According to the Fuel Injection Ratio of an Ultra-Lean LPG Direct Injection Engine

The effect of the fuel injection ratio on the combustion and emission characteristics of stratified lean mixture combustion was investigated for a spray-guided liquefied petroleum gas (LPG) direct injection engine. Inter-injection spark-ignition combustion—a specially designed combustion strategy for LPG fuel derived from a two-staged injection—was employed to maximize the improvement in thermal efficiency when combustion stability is secured. When changing the fuel injection ratio, the optimum spark advance and fuel injection timings were experimentally determined to maximize the thermal efficiency based on sweeping timings. The optimum fuel injection ratio with the highest thermal efficiency (42.76%) and stable operation was 60%/40%, with the optimization of the spark advance and fuel injection timing, because of the locally rich mixture region in the recirculation zone. NOx emissions were at their highest level with a fuel injection ratio of 60%/40% because of the high combustion temperature, and the levels of total hydrocarbon and CO emissions with 50%/50% and 60%/40% fuel injection ratios were similar, whereas emissions at 70%/30% were significantly higher because of fuel wetting and the formation of over-lean mixture

The Impact of Post-Mastectomy Radiotherapy on Survival Outcomes in Breast Cancer Patients Who Underwent Neoadjuvant Chemotherapy

This study aimed to determine whether post-mastectomy radiotherapy (PMRT) is beneficial for the prognosis of patients who achieved pathologic complete response (pCR), or who had minimal residual disease, after undergoing neoadjuvant chemotherapy (NAC). Patients who underwent a total mastectomy between 2006 and 2018, after NAC, were included. Patients who did not receive PMRT were matched using 1:3 propensity score matching (PSM). Kaplan–Meier survival curves were used to compare locoregional recurrence-free survival (LRRFS) and overall survival (OS). A total of 368 patients were included after 1:3 PSM. PMRT improved the LRRFS (p = 0.016) and OS (p = 0.017) rates of patients who underwent NAC. However, PMRT did not affect the prognosis of patients with pCR (LRRFS: p = 0.999; OS: p = 0.453). In addition, PMRT had a limited effect on LRRFS and OS in patients who responded well to NAC, with a neoadjuvant response index (NRI) value of 0.7–1.0 (LRRFS: p = 0.568; OS: p = 0.875). PMRT improved the OS of patients with a large residual tumor burden, such as nodal metastases or pathologic stage II/III. The benefits of PMRT vary depending on the patients’ response to NAC, although PMRT is useful for treating patients who underwent NAC. PMRT can be omitted, not only in patients with pCR, but also in good responders with an NRI value of 0.7–1.0

Association of LETM1 and mrpl36 contributes to the regulation of mitochondrial ATP production and necrotic cell death

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome, and was deleted in nearly all patients with the syndrome. LETM1 encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. Here, we describe LETM1-mediated regulation of mitochondrial ATP production and biogenesis. We show that LETM1 overexpression can induce necrotic cell death in HeLa cells, in which LETM1 reduces mitochondrial biogenesis and ATP production. LETM1 acts as an anchor protein and associates with mitochondrial ribosome protein L36. Adenovirus-mediated overexpression of LETM1 reduced mitochondrial mass and expression of many mitochondrial proteins. LETM1-mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling. The expression levels of LETM1 were significantly increased in multiple human cancer tissues compared with normals. These data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. The increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 is a key feature of tumorigenesis