PNUTS functions as a proto-oncogene by sequestering PTEN.

PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes, such as survival, growth, motility, invasiveness, and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN-associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared with matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene.

Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer.

Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46%) primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies.

Farber lipogranulomatosis: clinical and molecular genetic analysis reveals a novel mutation in an Indian family.

Farber disease is a rare lysosomal storage disorder caused by a deficiency of the acid ceramidase enzyme, leading to the accumulation of ceramide in various tissues. It usually manifests within a few months after birth with a unique triad of symptoms, including painful and progressive deformed joints, progressive hoarseness and subcutaneous nodules. The disease is inherited as an autosomal recessive trait, and mutations in the N-acylsphingosine amidohydrolase (ASAH1) gene, which codes for the acid ceramidase enzyme, have been shown to cause the disease. In the current study, we report the identification of a novel disease-causing mutation in the ASAH1 gene that results in Farber disease in an Indian family. The mutation was identified in the eighth exon and is a missense mutation resulting in replacement of Valine by Leucine at codon 182. Two affected siblings harboured the identical mutation. The possible mechanism(s) of disease caused by this mutation are discussed.