The direct metabolic and electrical coupling of cells by means of gap junctions has far significance for the integration of tissue function as a whole and specific relevance to the regulation of cell proliferation. Tumor and transformed cells typically show reduced coupling and many transforming agents (eg. oncogenes, tumor promotors) seem to down-regulate junctional expression. The reverse has also been reported for some anti-neoplastic agents (eg. retinoic acid). Clones (cDNA) to several of the known gap junction proteins have now been isolated and clearly show there to be a family of related proteins showing major differences in their regulatory domains. As a first step, the gap junctional channel structure and locations of functional domains on the protein subunits will be studied and compared between the various subtypes. Initial models will be tested and modified using results from in vitro manipulations (eg. phosphorylation), peptide analyses, and site specific antibodies. Functional effects on the junctions will be monitored electrophysiologically in isolated preparations employing the """"""""tip- patch"""""""" technique, or in situ in cultured cells. Refinement of these models will be achieved by expression of the proteins in frog oocytes, and subsequently testing the effects of oligonucleotide directed mutations on intercellular channel function. These studies will serve to better describe channel structure, selectivity (if found in the various subtypes) and modes of regulation. Parallel experiments will use conserved and variable region probes from the junctional cDNA's to determine the approximate size of the gene family and the patterns of expression of the different junction subtypes before and after the transformation process, including their distribution within selected tumors. Finally, the two lines of investigation will be combined by transforming cells with expression vectors containing the junctional cDNA's (in both sense and antisense orientations) and directly testing the necessity or sufficiency of junctional downregulation in the process of transformation and metastatic invasion of issue.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University of New York at Buffalo
Schools of Arts and Sciences
United States
Zip Code
Polusani, Srikanth R; Kalmykov, Edward A; Chandrasekhar, Anjana et al. (2016) Cell coupling mediated by connexin 26 selectively contributes to reduced adhesivity and increased migration. J Cell Sci 129:4399-4410
Chandrasekhar, Anjana; Kalmykov, Edward A; Polusani, Srikanth R et al. (2013) Intercellular redistribution of cAMP underlies selective suppression of cancer cell growth by connexin26. PLoS One 8:e82335
Xu, Ji; Nicholson, Bruce J (2013) The role of connexins in ear and skin physiology - functional insights from disease-associated mutations. Biochim Biophys Acta 1828:167-78
Mitra, Siddhartha S; Xu, Ji; Nicholson, Bruce J (2012) Coregulation of multiple signaling mechanisms in pp60v-Src-induced closure of Cx43 gap junction channels. J Membr Biol 245:495-506
Oshima, Atsunori; Tani, Kazutoshi; Toloue, Masoud M et al. (2011) Asymmetric configurations and N-terminal rearrangements in connexin26 gap junction channels. J Mol Biol 405:724-35
Ambrosi, Cinzia; Boassa, Daniela; Pranskevich, Jennifer et al. (2010) Analysis of four connexin26 mutant gap junctions and hemichannels reveals variations in hexamer stability. Biophys J 98:1809-19
Martínez, Agustín D; Acuña, Rodrigo; Figueroa, Vania et al. (2009) Gap-junction channels dysfunction in deafness and hearing loss. Antioxid Redox Signal 11:309-22
Beahm, Derek L; Oshima, Atsunori; Gaietta, Guido M et al. (2006) Mutation of a conserved threonine in the third transmembrane helix of alpha- and beta-connexins creates a dominant-negative closed gap junction channel. J Biol Chem 281:7994-8009
Sosinsky, Gina E; Nicholson, Bruce J (2005) Structural organization of gap junction channels. Biochim Biophys Acta 1711:99-125
Chandrasekhar, A; Merritt, M; Huh, S J et al. (2004) Connexin expression and cell coupling fail to reverse the v-src transformed growth characteristics of a Cx43-/- cell line. Cell Commun Adhes 11:103-19

Showing the most recent 10 out of 25 publications