Connexins (Cx) which constitute space junction intercellular channels in vertebrates have

Connexins (Cx) which constitute space junction intercellular channels in vertebrates have been shown to suppress transformed cell growth and tumorigenesis but the mechanism(s) still remain largely speculative. appeared to result from a redistribution of cAMP throughout the cell population removing the cell cycle oscillations in cAMP required for efficient cell cycle progression. Cx43 and Cx32 fail to mediate this redistribution as unlike Cx26 these channels are closed during the G2/M phase of the cell cycle when cAMP levels peak. Comparisons of tumor cell lines show that this is definitely a general pattern with growth suppression by connexins happening whenever cAMP oscillates with the cell cycle and the space junction remain open throughout the cell cycle. Thus space junctional coupling in the absence of any K252a external signals provides a general means to limit the mitotic rate of cell populations. Intro Space junctions are arrays of intercellular channels that are the only mediators of direct intercellular exchange of small metabolites and signaling molecules in multicellular systems [1 2 In vertebrates these channels are composed of integral membrane proteins called connexins (Cx) with four transmembrane domains and cytoplasmic N and C -termini. Six connexins come together to form a hemichannel or connexon and two such hemichannels from opposing cells dock to produce the intercellular space junction channel [3]. The integral but specialized part of space junctions in assorted tissues VCA-2 is definitely facilitated by the presence of at least 21 different connexin isoforms in humans with unique proteins that are K252a classified according to their molecular excess weight [4] and a gene nomenclature explained in [5]. The Cx43 Cx32 and Cx26 proteins analyzed here are encoded from the K252a and genes respectively. Almost since their finding space junctions have been implicated as tumor suppressors in several tissues [6]. This has been confirmed in genetic screens of numerous tumor types including breast carcinoma [7] prostate malignancy [8] and melanoma [9]. A multitude of tumor types and transformed cell lines demonstrate decreased connexin protein manifestation and/or space junction features (examined in 10). Furthermore there are several documented cases where the exogenous manifestation of connexins inside a transformed cell collection can dramatically suppress its transformed properties and its ability to form tumors in nude mice [Cx43 in C6 glioma cells [11]; Cx43 in 10T1/2 embryonic mesenchymal cells [12]; Cx43 and Cx32 in LNCaP prostate malignancy cells [13]; Cx26 in HeLa cervical malignancy cells [14]; Cx26 and Cx43 in MDA-MB-231 breast malignancy cells [15 16 and; Cx32 in SKHep1 hepatoma cells [17]. The second option is also consistent with an increase in hepatic tumorigenesis observed in Cx32-/- mice [8 18 Growth suppression of transformed cells by Cx manifestation has been linked to rules of pro- and anti-apoptotic proteins (e.g. Bcl-2) [19 20 or changes in cell cycle proteins such as NOV (CCN3) [21] K252a Skp2 [22] and p21 [23 24 However establishing a direct connection between any of these events and the exchange of signaling molecules between cells through space junctions has verified elusive. Progress in this regard has been restricted by limited info on both the permeability properties of connexins and the spatio-temporal distribution of low molecular excess weight metabolite concentrations in multicellular populations. In some cases connexins have been proposed to suppress growth actually in the absence of demonstrable space junction channel activity [15 21 24 25 ]. This could occur through relationships with additional K252a proteins known to bind to connexins (examined by [26]) through their function as hemichannels which can contribute to improved cell death [27] and even through mis-localization of parts of the protein (25). However definitive links between any of these processes and anti-oncogenic factors remain to be established. While the part of cell coupling compared to additional connexin functions is still a subject for argument in tumor suppression the link between space junction coupling and mitogenesis has been established in several nonpathogenic conditions. Several growth factors such as EGF [28] and PDGF [12] have been shown to induce transient uncoupling of cells as part of the immediate early response that precedes initiation of mitosis. Oncogenes like have been shown to possess similar but more long-lasting effects on coupling [29]. X-OMAT Processor.