Tumours and tremors: how PTEN regulation underlies both

Mutations of the tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) are seen in many human cancers. However, dysregulation of PTEN may be involved in other disease states such as Parkinson's disease. This minireview describes recent work examining PTEN regulation and its implications for the development of both cancer and neurodegenerative disease

A Whole-Genome SNP Association Study of NCI60 Cell Line Panel Indicates a Role of Ca2+ Signaling in Selenium Resistance

Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33–34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis

Insulin-like growth factor 1 signaling regulates cytosolic sialidase Neu2 expression during myoblast differentiation and hypertrophy.

Cytosolic sialidase (neuraminidase 2; Neu2) is an enzyme whose expression increases during myoblast differentiation. Here we show that insulin-like growth factor 1 (IGF1)-induced hypertrophy of myoblasts notably increases Neu2 synthesis by activation of the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (P13K/AKT/mTOR) pathway, whereas the proliferative effect mediated by activation of the extracellular regulated kinase 1/2 (ERK1/2) pathway negatively contributed to Neu2 activity. Accordingly, the differentiation L6MLC/IGF-1 cell line, in which the forced postmitotic expression of insulin-like growth factor 1 stimulates a dramatic hypertrophy, was accompanied by a stronger Neu2 increase. Indeed, the hypertrophy induced by transfection of a constitutively activated form of AKT was able to induce high Neu2 activity in C2C12 cells, whereas the transfection of a kinase-inactive form of AKT prevented myotube formation, triggering Neu2 downregulation. Neu2 expression was strictly correlated with IGF-1 signaling also in C2 myoblasts overexpressing the insulin-like growth factor 1 binding protein 5 and therefore not responding to endogenously produced insulin-like growth factor 1. Although Neu2-transfected myoblasts exhibited stronger differentiation, we demonstrated that Neu2 overexpression does not override the block of differentiation mediated by PI3 kinase and mTOR inhibitors. Finally, Neu2 overexpression did not modify the ganglioside pattern of C2C12 cells, suggesting that glycoproteins might be the target of Neu2 activity. Taken together, our data demonstrate that IGF-1-induced differentiation and hypertrophy are driven, at least in part, by Neu2 upregulation and further support the significant role of cytosolic sialidase in myoblasts