Connexins: sensors and regulators of cell cycling (original) (raw)
Related papers
2007
Cell proliferation is an important process for reproduction, growth and renewal of living cells and occurs in several situations during life. Cell proliferation is present in all the steps of carcinogenesis, initiation, promotion and progression. Gap junctions are the only specialization of cell membranes that allows communication between adjacent cells. They are known to contribute to tissue homeostasis and are composed of transmembrane proteins called ''connexins.'' These junctions are also known to be involved in cell proliferation control. The roles of gap junctions and connexins in cell proliferation are complex and still under investigation. Since pioneer studies by Loewenstein, it is known that neoplastic cells lack communicating junctions. They do not communicate with their neighbors or with non-neoplastic cells from the surrounding area. There are many studies and review articles dedicated to neoplastic tissues. The aim of this review is to present evidence on the roles of gap junctions and connexins in non-neoplastic processes in which cell proliferation is involved.
Connexins: a myriad of functions extending beyond assembly of gap junction channels
Cell Commun …, 2009
Connexins constitute a large family of trans-membrane proteins that allow intercellular communication and the transfer of ions and small signaling molecules between cells. Recent studies have revealed complex translational and post-translational mechanisms that regulate connexin synthesis, maturation, membrane transport and degradation that in turn modulate gap junction intercellular communication. With the growing myriad of connexin interacting proteins, including cytoskeletal elements, junctional proteins, and enzymes, gap junctions are now perceived, not only as channels between neighboring cells, but as signaling complexes that regulate cell function and transformation. Connexins have also been shown to form functional hemichannels and have roles altogether independent of channel functions, where they exert their effects on proliferation and other aspects of life and death of the cell through mostly-undefined mechanisms. This review provides an updated overview of current knowledge of connexins and their interacting proteins, and it describes connexin modulation in disease and tumorigenesis.
Gap junction- and hemichannel-independent actions of connexins
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2005
Connexins have been known to be the protein building blocks of gap junctions and mediate cell-cell communication. In contrast to the conventional dogma, recent evidence suggests that in addition to forming gap junction channels, connexins possess gap junction-independent functions. One important gap junction-independent function for connexins is to serve as the major functional component for hemichannels, the un-apposed halves of gap junctions. Hemichannels, as independent functional units, play roles that are different from that of gap junctions in the cell. The other functions of connexins appear to be gap junction-and hemichannel-independent. Published studies implicate the latter functions of connexins in cell growth, differentiation, tumorigenicity, injury, and apoptosis, although the mechanistic aspects of these actions remain largely unknown. In this review, gap junction-and hemichannel-independent functions of connexins are summarized, and the molecular mechanisms underlying these connexin functions are speculated and discussed.
Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics
International Journal of Molecular Sciences
Since their characterization more than five decades ago, gap junctions and their structural proteins-the connexins-have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. It appeared that if gap junctions or connexins can down regulate cancer cell growth they can be also implied in the migration, invasion and metastatic dissemination of cancer cells. Interestingly, in all these situations, connexins seem to be involved through various mechanisms in which they can act either as gap-junctional intercellular communication mediators, modulators of signalling pathways through their interactome, or as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in cancer progression is even more complicated by the fact that their hemichannel function may overlap with other gap junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed.
Biological role of connexin intercellular channels and hemichannels
Archives of Biochemistry and Biophysics, 2012
Gap junctions (GJ) and hemichannels (HC) formed from the protein subunits called connexins are transmembrane conduits for the exchange of small molecules and ions. Connexins and another group of HC-forming proteins, pannexins comprise the two families of transmembrane proteins ubiquitously distributed in vertebrates. Most cell types express more than one connexin or pannexin. While connexin expression and channel activity may vary as a function of physiological and pathological states of the cell and tissue, only a few studies suggest the involvement of pannexin HC in acquired pathological conditions. Importantly, genetic mutations in connexin appear to interfere with GJ and HC function which results in several diseases. Thus connexins could serve as potential drug target for therapeutic intervention. Growing evidence suggests that diseases resulting from HC dysfunction might open a new direction for development of specific HC reagents. This review provides a comprehensive overview of the current studies of GJ and HC formed by connexins and pannexins in various tissue and organ systems including heart, central nervous system, kidney, mammary glands, ovary, testis, lens, retina, inner ear, bone, cartilage, lung and liver. In addition, present knowledge of the role of GJ and HC in cell cycle progression, carcinogenesis and stem cell development is also discussed. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y a b b i
Connexins in cancer: bridging the gap to the clinic
Oncogene, 2019
Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide for the direct communication between adjacent cells. This type of intercellular communication permits the coordination of cellular activities and plays key roles in the control of cell growth and differentiation and in the maintenance of tissue homoeostasis. After more than 50 years, deciphering the links among connexins, gap junctions and cancer, researchers are now beginning to translate this knowledge to the clinic. The emergence of new strategies for connexin targeting, combined with an improved understanding of the molecular bases underlying the dysregulation of connexins during cancer development, offers novel opportunities for clinical applications. However, different connexin isoforms have diverse channel-dependent and-independent functions that are tissue and stage specific. This can elicit both pro-and anti-tumorigenic effects that engender significant challenges in the path towards personalised medicine. Here, we review the current understanding of the role of connexins and gap junctions in cancer, with particular focus on the recent progress made in determining their prognostic and therapeutic potential.
Toxicology Letters, 1998
Evidence is accumulating that connexin (Cx) genes form a family of tumor-suppressor genes. Our long-standing study revealed that, in almost all tumors, some abnormality in gap junction is observed, including loss or reduction of expression, aberrant localization of gap junction. In this study, we have examined the dominant-negative effects of mutant (prepared by site-directed mutagenesis) Cx43 constructs in C6 glioma cells, and of mutant Cx26 constructs in HeLa cells, on tumorigenicity. The mutant Cx43 A253V (Ala 253 to Val) inhibited the tumor-suppressive function exerted by wild-type Cx43 in C6 cells. Similarly, the mutant Cx26 P87L (Pro 87 to Leu) manifested dominant-negative inhibition of connexin-mediated cell growth control in HeLa cells. These results suggest that mutations of connexin genes can affect the tumor-suppressive function of gap junction and that gap junctional intercellular communication can be regulated by not only non-genotoxic but also genotoxic activities of environmental carcinogens.
Journal of Membrane Biology, 2007
The constituent proteins of gap junctions, called ''connexins'' (Cxs) in chordates, are generally renewed several times a day, in approximately the same rate range as many other integral plasma membrane proteins and the proteins of other channels, other intercellular junctions or different membrane receptors. This permanent renewal turns on a fine-tuned balance among various processes, such as gene transcription, mRNA stability and processing, protein synthesis and oligomerization, posttranslational modifications, transport to the plasma membrane, anchoring to the cytoskeleton, connexon aggregation and docking, regulation of endocytosis and controlled degradations of the proteins. Subtle changes at one or some of these steps would represent an exquisite level of regulation that extends beyond the rapid channel opening and closure events associated with channel gating; membrane channels and receptors are constantly able to answer to physiological requirements to either up-or downregulate their activity. The Cx turnover rate thereby appears to be a key component in the regulation of any protein, particularly of gap junctional proteins. However, the physiological stimuli that control the assembly of Cxs into gap junctions and their degradation remain poorly understood.