Beyond γ-secretase activity: The multifunctional nature of presenilins in cell signalling pathways.

The presenilins are the catalytic subunit of the membrane-embedded tetrameric γ-secretase protease complexes. More that 90 transmembrane proteins have been reported to be γ-secretase substrates, including the widely studied amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β peptides and biologically active APP intracellular domain (AICD) and Notch intracellular domain (NICD). The diversity of γ-secretase substrates highlights the importance of presenilin-dependent γ-secretase protease activities as a regulatory mechanism in a range of biological systems.

Gamma-secretase-independent role for cadherin-11 in neurotrophin receptor p75 (p75(NTR)) mediated glioblastoma cell migration.

The p75 neurotrophin receptor (p75(NTR)) undergoes γ-secretase-mediated regulated intramembrane proteolysis and is involved in glioblastoma cell migration and invasion. Consistent with previous reports, in this study we show that p75NTR increases U87-MG glioblastoma cell migration, which is reversed by inhibition of γ-secretase activity. However, we show that expression or stabilization of the γ-secretase-generated p75(NTR) intracellular domain (ICD) is not sufficient to induce U87-MG glioblastoma cell migration, and that exogenous expression of p75(NTR) ICD inhibits p75(NTR)-mediated glioblastoma cell (U87-MG and U373-MG) migration.

A ubiquitin-binding CUE domain in presenilin-1 enables interaction with K63-linked polyubiquitin chains.

The presenilins (PS1 and PS2) are the catalytic component of the γ-secretase intramembrane protease complex, involved in the regulated intramembrane proteolysis of numerous type I transmembrane proteins, including amyloid precursor protein (APP) and Notch. Herein, we describe the identification and characterization of a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin-binding domain (UBD) in PS1, and demonstrate that the CUE domain of PS1 mediates non-covalent binding to Lysine 63-linked polyubiquitin chains. Our results highlight a γ-secretase-independent function for non-covalent ubiquitin signaling in the regulation of PS1, and add new insights into the structure and function of the presenilin proteins.

Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer.

Purpose: Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5alpha-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC).

Experimental Design: Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.

Radical prostatectomy lowers plasma vascular endothelial growth factor levels in patients with prostate cancer.

Objectives: To measure the change in plasma vascular endothelial growth factor (VEGF) levels after radical prostatectomy (RP) and to examine the association of pre-RP VEGF levels with known prognostic factors.

Methods: Plasma was collected from patients in two separate cohorts. The first cohort included 86 patients who consented to give blood before and after RP.

Minimal effect of a low-fat/high soy diet for asymptomatic, hormonally naive prostate cancer patients.

Purpose: The effects of a low-fat diet or a low-fat diet with the addition of a soy supplement were investigated in a pilot Phase II study for asymptomatic, hormonally naive prostate cancer patients with rising prostate-specific antigen (PSA) levels.

Experimental Design: A two-step intervention was implemented. During step 1 patients were begun on a low-fat diet with a goal to reduce fat intake to 15% of total daily calories.

Serum levels of insulin-like growth factor-1 and insulin-like growth factor-1 binding proteins after radical prostatectomy.

Purpose: Elevated serum levels of insulin-like growth factor-1 (IGF-1) have been consistently shown to be a risk factor for prostate cancer. Alterations in serum IGF-1 binding proteins 1 to 3 have also been associated with prostate cancer risk. A potentially important complication in these studies is that prostate tissue, perhaps especially malignant prostate tissue, may secrete IGF-1 and its binding proteins into serum.