Cadherin and catenin alterations in human cancer

Among the hallmarks of cancer are defective cell-cell and cell-matrix adhesion. Alterations in cadherin-catenin complexes likely have a major contributing role in cell-adhesion defects in carcinomas arising in many different tissues. E-cadherin, the prototypic member of the cadherin transmembrane protein family, regulates cell adhesion by interacting with E-cadherin molecules on opposing cell surfaces. E-cadherin's function in cell adhesion is also critically dependent on its ability to interact through its cytoplasmic domain with catenin proteins. A diverse collection of defects alter cadherin-catenin function in cancer cells, including loss-of-function mutations and defects in the expression of E-cadherin and certain catenins, such as alpha-catenin. Although there is much evidence that beta-catenin is deregulated in cancer as a result of inactivating mutations in the APC and AXIN tumor-suppressor proteins and gain-of-function mutations in beta-catenin itself, the principal consequences of beta-catenin deregulation in cancer appear to be largely distinct from the effects attributable to inactivation of E-cadherin or alpha-catenin. In this review, we highlight some of the specific genetic and epigenetic defects responsible for altered cadherin and catenin function in cancer, as well as potential contributions of cadherin-catenin alterations to the cancer process.     

Modulation of recombinant T-type Ca2+ channels by hypoxia and glutathione

T-type Ca2+ channels are expressed in a wide variety of central and peripheral neurons and play an important role in neuronal firing and rhythmicity. Here we examined the effects of hypoxia on the recently cloned T-type Ca2+ channel alpha1G, alpha1H and alpha1I subunits, stably expressed in HEK 293 cells. In cells expressing the human alpha1H or the rat alpha1I subunit, Ca2+ channel currents were inhibited reversibly by hypoxia (PO2<110 mm Hg). The degree of inhibition was more marked in cells expressing the a1H subunit. This hypoxic inhibition was not voltage dependent. In cells expressing the rat alpha1G subunit, hypoxia caused no detectable reduction in Ca2+ channel activity. Regardless of the channel type examined, hypoxia was without effect on the kinetic properties of the Ca2+ current (activation, inactivation and deactivation) or on steady-state inactivation. Ca2+ current through the alpha1H subunit was enhanced by the reducing agent reduced glutathione (GSH; 2 mM) and inhibited by oxidised glutathione (GSSG; 2 mM). In contrast, Ca2+ current through the alpha1G subunit was unaffected by GSH. In alpha1H cells, neither GSH nor GSSG had any effect on the ability of hypoxia to reduce Ca2+ current amplitudes. Thus, different members of the T-type Ca2+ channel family are differently regulated by hypoxia and redox agents. Hypoxic regulation of the alpha1H subunit appears to be independent of changes in levels of the intracellular redox couple GSSG:GSH.