The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction.

In response to proteasome dysfunction, mammalian cells upregulate proteasome gene expression by activating Nrf1. Nrf1 is an endoplasmic reticulum-resident transcription factor that is continually retrotranslocated and degraded by the proteasome. Upon proteasome inhibition, Nrf1 escapes degradation and is cleaved to become active. However, the processing enzyme for Nrf1 remains obscure. Here we show that the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is required to cleave and activate Nrf1. Deletion of DDI2 reduced the cleaved form of Nrf1 and increased the full-length cytosolic form of Nrf1, resulting in poor upregulation of proteasomes in response to proteasome inhibition. These defects were restored by adding back wild-type DDI2 but not protease-defective DDI2. Our results provide a clue for blocking compensatory proteasome synthesis to improve cancer therapies targeting proteasomes.

Differences in gene expression in the proliferative human endometrium.

OBJECTIVE: To use microdissection and DNA microarray technology to demonstrate differences in gene expression between epithelial and stromal areas in the proliferative human endometrium. DESIGN: Pilot study. SETTING: University hospital. PATIENT(S): Patients with normal menstrual cycles and at least one previous intrauterine pregnancy. INTERVENTION(S): Uterine endometrial biopsy. MAIN OUTCOME MEASURE(S): Gene expression. RESULT(S): From a total of 1,200 genes, 14 were strongly expressed in epithelial areas and 12 were strongly expressed in stromal areas. Among the genes strongly expressed in the stroma, expressions of decorin and discoidin domain receptor were confirmed by real-time polymerase chain reaction. Decorin was localized in the stromal areas by immunohistochemical staining. To confirm the effects of estrogen on gene expression, stromal cells were cultured. When E(2) was added to the culture media, expression of decorin mRNA was increased. CONCLUSION(S): The data demonstrated in this study help to understand the physiology of human endometrium. Decorin was strongly expressed in the stromal areas and was regulated by estrogen, and therefore it may be involved in restoration of the endometrium.

[Serious renal infection: report of three cases].

In renal infections, lack of peculiar symptoms and consequent delay of diagnosis can sometimes lead to a critical condition of the patient. We report three cases of life-threatening renal infections in female patients, two of which were subsequently fata. One patient died of left emphysematous pyelonephritis with bilateral pleuritis. The patient was correctly diagnosed 13 days after the onset of symptoms and expired 2 months later despite nephrectomy on the day of diagnosis. The second patient died of septic shock 3 days following the onset of symptoms. Autopsy revealed multiple perinephric abscess of the left kidney. The non-fatal case was a perinephric abscess spread to the iliopsoas muscle. The patient was diagnosed with perinephric abscess 11 days after the onset of symptoms and eventually underwent nephrectomy 9 days later. Two of the patients were diabetics and the third was a probable diabetic, who died too suddenly to confirm the diagnosis. Herein, we review the literature of, and discuss the diagnosis and management of serious renal infection.