Abstract
Gap junctional, intercellular communication (GJIC) is interrupted in cells transformed by oncogenes such as activated Src. The Src effector, Ras, is required for this effect, so that Ras inhibition restores GJIC in Src-transformed cells. Interestingly, the inhibition of the Src effector phosphatidyl-inositol-3 kinase (PI3k) or Signal Transducer and Activator of Transcription-3 (Stat3) pathways does not restore GJIC. In the contrary, inhibition of PI3k or Stat3 in non-transformed rodent fibroblasts or epithelial cells or certain human lung carcinoma lines with extensive GJIC inhibits communication, while mutational activation of PI3k or Stat3 increases GJIC. Therefore, it appears that oncogenes such as activated Src have a dual role upon GJIC; acting as inhibitors of communication through the Ras pathway, and as activators through activation of PI3k or Stat3. In the presence of high Src activity the inhibitory functions prevail so that the net effect is gap junction closure. PI3k and Stat3 constitute potent survival signals, so that their inhibition in non-transformed cells triggers apoptosis which, in turn, has been independently demonstrated to suppress GJIC. The interruption of gap junctional communication would confine the apoptotic event to single cells and this might be essential for the maintenance of tissue integrity. We hypothesize that the GJIC activation by PI3k or Stat3 may be linked to their survival function.
Highlights
Oncogenes and Gap Junctional CommunicationGap junctions are aqueous channels connecting the cytoplasm of adjacent cells that permit the passage of small molecules and ions [1,2]
The phosphatidyl-inositol-3 kinase (PI3k [29]) and the Signal Transducer and Activator of Transcription-3 (Stat3 [30]). Since both PI3k and Stat3 are required for transformation and in an activated form can act as oncogenes, we and others set out to examine the effect of PI3k and Stat3 upon the gap junctional communication apparatus
The results revealed that, despite the general acceptance of oncogenes as GJIC suppressors, PI3k and Stat3, rather than suppress, they are required for the maintenance of communication and in an activated form they increase GJIC [4,31,32]
Summary
Gap junctions are aqueous channels connecting the cytoplasm of adjacent cells that permit the passage of small molecules and ions [1,2]. Cancers 2019, 11, 167 connexin, growth suppression is likely caused by the C-terminal domain [9,10], and the effect can be through regulation of transcription, as well as cell to cell communication [11,12]. The phosphatidyl-inositol-3 kinase (PI3k [29]) and the Signal Transducer and Activator of Transcription-3 (Stat3 [30]) Since both PI3k and Stat are required for transformation and in an activated form can act as oncogenes, we and others set out to examine the effect of PI3k and Stat upon the gap junctional communication apparatus. In this report we integrate some recent findings on the effect of PI3k and Stat upon GJIC
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