Valosin-containing protein (VCP; p97; cdc48 in yeast) is a hexameric ATPase of the AAA family (ATPases with multiple cellular activities) involved in multiple cellular functions, including degradation of proteins by the ubiquitin (Ub)-proteasome system (UPS). We examined the consequences of the reduction of VCP levels after RNA interference (RNAi) of VCP. A new stringent method of microarray analysis demonstrated that only four transcripts were nonspecifically affected by RNAi, whereas ϳ30 transcripts were affected in response to reduced VCP levels in a sequence-independent manner. These transcripts encoded proteins involved in endoplasmic reticulum (ER) stress, apoptosis, and amino acid starvation. RNAi of VCP promoted the unfolded protein response, without eliciting a cytosolic stress response. RNAi of VCP inhibited the degradation of R-GFP (green fluorescent protein) and Ub-G76V -GFP, two cytoplasmic reporter proteins degraded by the UPS, and of ␣ chain of the T-cell receptor, an established substrate of the ER-associated degradation (ERAD) pathway. Surprisingly, RNAi of VCP had no detectable effect on the degradation of two other ERAD substrates, ␣1-antitrypsin and ␦CD3. These results indicate that VCP is required for maintenance of normal ER structure and function and mediates the degradation of some proteins via the UPS, but is dispensable for the UPS-dependent degradation of some ERAD substrates.
Laparoscopic ileocolic resection for CD is feasible. There are significant postoperative benefits in terms of resolution of ileus, narcotic use, and hospital stay. This approach translates into cost savings of >$3300 for laparoscopic patients.
We conclude that the diagnosis and presentation of atypical smoldering diverticular disease is an uncommon and poorly defined entity. However, sigmoid resection in this subgroup of patients is safe and is associated with resolution of symptoms in the majority of cases.
Simultaneous deregulation of both Wnt and ErbB growth factors has previously been shown to result in the cooperative induction of mammary gland tumors. Using the murine mammary tumor virus (MMTV)-Wnt-1 transgenic model of mammary carcinoma, we have identified an unvarying association between -catenin and epidermal growth factor receptor/c-Neu (ErbB1/ErbB2) heterodimers in mammary gland tumors, indicating a requirement for ErbB signaling in Wnt-mediated tumorigenesis. Expansion of these observations to a second transgenic model, MMTV-c-Neu, demonstrated similar tumor-specific interactions, including an ErbB1 ligandinducible phosphorylation of both -catenin and c-Neu. Direct relevance of these findings to human breast cancer was established upon examination of a set of human infiltrating ductal breast adenocarcinoma and lymph node metastasis tissues taken at surgery. These data revealed increased levels of -catenin in tumors and metastases versus normal breast as well as an association between -catenin and c-Neu that measurably occurs only in neoplasia, most strongly in metastatic lesions. These studies have identified a seemingly indispensable interaction between -catenin and epidermal growth factor receptor/c-Neu heterodimers in Wnt-1-mediated breast tumorigenesis that may indicate a fundamental signaling event in human metastatic progression.The ErbB family of transmembrane receptor tyrosine kinases (ErbB1 or epidermal growth factor receptor (EGFR), 1 ErbB2 or Her2/c-Neu, ErbB3, and ErbB4) and ligands (including EGF-like ligands and neuregulin-like ligands) have been consistently implicated in mammary gland tumorigenesis in both humans and rodents (1-3). The ErbB receptors are activated by the binding of cognate ligands, resulting in homo-and heterodimer receptor formation and subsequent phosphorylation of a wide variety of cellular substrates (i.e. mitogen-activated protein kinase, signal transducers and activators of transcription, phospholipase C␥, c-src, etc. (4)), most often leading to increased cellular mitogenesis. The development of transgenic lines targeting overexpression of either the ligands (3) or the receptors (5, 6) to the mammary gland invariably results in tumorigenesis and has been useful in elucidating the involvement of other proteins in ErbB-related oncogenesis, such as c-Myc (7) and cyclin D1 (8). One such study utilized insertional mutagenesis of the WAP-transforming growth factor ␣ (TGF␣) model to identify genes able to synergize with EGFR activation in tumor progression (9). These studies resulted in the observation that Wnt-1 and Wnt-3 are up-regulated in this model of ErbB-induced tumorigenesis, indicating that these pathways may cooperate during transformation.The Wnts are a family of secreted proteins whose overexpression results in the accumulation of -catenin, a protein involved in both cellular adhesion (as a critical component of the E-cadherin-actin complex found at adherens junctions) and oncogenesis (10, 11). Binding of the soluble Wnt protein to the Frizzled receptor r...
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