The carboxy-tail of connexin-43 localizes to the nucleus and inhibits cell growth

Dang, Xitong; Doble, Bradley W.; Kardami, Elissavet

doi:10.1007/978-1-4757-4712-6_5

Cited by 122 publications

(97 citation statements)

References 10 publications

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“…For example, it has been shown that Cx43 can be localized in the nucleus, which can be explained by the existence of a putative nuclear targeting sequence in the carboxy-terminal of Cx43. Additionally, growing evidence suggests that the nuclear presence of Cx43 is associated with its role as gene expression regulator (43). Our report shows that Cx43 interacts with a wide variety of heterogeneous nuclear ribonucleoproteins (hnRNP), which can function upon transcription, splicing, mRNA trafficking or translational silencing.…”

Section: Ischemia Affects the Interaction Of Cx43 With Regulators Of mentioning

confidence: 78%

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

Martins‐Marques

Anjo

Pereira

et al. 2015

Molecular & Cellular Proteomics

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The coordinated and synchronized cardiac muscle contraction relies on an efficient gap junction-mediated intercellular communication (GJIC) between cardiomyocytes, which involves the rapid anisotropic impulse propagation through connexin (Cx)-containing channels, namely of Cx43, the most abundant Cx in the heart. Expectedly, disturbing mechanisms that affect channel activity, localization and turnover of Cx43 have been implicated in several cardiomyopathies, such as myocardial ischemia. Besides gap junction-mediated intercellular communication, Cx43 has been associated with channel-independent functions, including modulation of cell adhesion, differentiation, proliferation and gene transcription. It has been suggested that the role played by Cx43 is dictated by the nature of the proteins that interact with Cx43. Therefore, the characterization of the Cx43-interacting network and its dynamics is vital to understand not only the molecular mechanisms underlying pathological malfunction of gap junction-mediated intercellular communication, but also to unveil novel and unanticipated biological functions of Cx43. In the present report, we applied a quantitative SWATH-MS approach to characterize the Cx43 interactome in rat hearts subjected to ischemia and ischemiareperfusion. Our results demonstrate that, in the heart, Cx43 interacts with proteins related with various biological processes such as metabolism, signaling and trafficking.

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Section: Ischemia Affects the Interaction Of Cx43 With Regulators Of mentioning

confidence: 78%

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

Martins‐Marques

Anjo

Pereira

et al. 2015

Molecular & Cellular Proteomics

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“…However, they contrast with previous data from other cells suggesting that induction of apoptosis by different inducers was influenced by properties of Cx43 other than gap junction function (Huang et al, 2001). For example, expression of the Cterminal domain of Cx43 suppresses the growth of Neuro2A (Moorby and Patel, 2001) and HeLa cells (Dang et al, 2003). Moreover, retrovirally-delivered Cx26 suppresses the growth of breast cancer tumors in mice without restoring intercellular communication (Qin et al, 2002).…”

Section: Journal Of Cell Science 120 (2)mentioning

confidence: 99%

Connexin43 increases the sensitivity of prostate cancer cells to TNFα-induced apoptosis

Wang

Berthoud

Beyer

2007

Journal of Cell Science

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To examine the effects of increased expression of connexin43 (Cx43) upon cell viability and response to cytotoxic agents, we expressed Cx43 in LNCaP and PC3 prostate cancer cells by infection with a recombinant adenovirus (Ad-Cx43). Infection with Ad-Cx43 led to the formation of Cx43-containing gap junction plaques at appositional membranes and increased Lucifer Yellow transfer in LNCaP cells, but not in PC3 cells. The increased intercellular communication was blocked by co-infection with an adenovirus containing a dominant-negative Cx43 (Ad-Cx43DN). Infection of LNCaP (but not PC3) cells with Ad-Cx43 greatly increased their sensitivity to killing by tumor necrosis factor α (TNFα), anti-Fas antibodies, and TRAIL as quantified using an MTS assay. The TNFα-induced cell death was dependent on cell density, and it was associated with increased annexin V staining, an increased proportion of sub-G1 cells, and activation of caspase 8. The TNFα-induced effects on Ad-Cx43-infected LNCaP cells were blocked by co-infection with Ad-Cx43DN or by pre-incubation with neutralizing antibodies directed against TNFα receptor 1. These results demonstrate that TNFα induces apoptosis in LNCaP cells by signaling through TNFα receptor 1 and that expression of functional Cx43 gap junction channels increases their sensitivity to TNFα.

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“…There are several reports indicating gap-junction-independent roles for connexins in the control of cell growth and the suppression of tumorigenicity (Mesnil et al, 1995;Huang et al, 1998;Duflot-Dancer et al, 1997;Omori and Yamasaki, 1998;Olbina and Eckhart, 2003;Jiang and Gu, 2005). In two reports, the Cterminal domain of Cx43 alone is sufficient to suppress cell growth (Moorby and Patel, 2001;Dang et al, 2003).…”

Section: Journal Of Cell Science 120 (20)mentioning

confidence: 99%

Promotion of lens epithelial-fiber differentiation by the C-terminus of connexin 45.6 – a role independent of gap junction communication

Banks¹,

Yu²,

Shi³

et al. 2007

Journal of Cell Science

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We previously reported that, among the three connexins expressed in chick lens, overexpression of connexin (Cx) 45.6, not Cx43 or Cx56, stimulates lens cell differentiation; however, the underlying mechanism responsible for this effect is unclear. Here, we took advantage of naturally occurring loss-of-gap-junction function mutations of Cx50 (ortholog of chick Cx45.6) and generated the corresponding site mutants in Cx45.6: Cx45.6(D47A) and Cx45.6(P88S). In contrast to wild-type Cx45.6, the mutants failed to form functional gap junctions, and Cx45.6(P88S) and, to a lesser degree, Cx45.6(D47A) functioned in a dominant-negative manner. Interestingly, overexpression of both mutants incapable of forming gap junctions significantly increased epithelial-fiber differentiation to a level comparable to that of wild-type Cx45.6. To map the functional domain of Cx45.6, we generated a C-terminus chimera as well as deletion mutants. Overexpression of Cx56*45.6C, the mutant in which the C-terminus of Cx56 was replaced with that of Cx45.6, had a stimulatory effect on lens cell differentiation similar to that of Cx45.6. However, cells overexpressing Cx45.6*56C, the mutant in which C-terminus of Cx45.6 was replaced with that of Cx56, and Cx45.6(-C), in which the C-terminus was deleted, failed to promote differentiation. Taken together, we conclude that the expression of Cx45.6, but not Cx45.6-dependent gap junction channels, is involved in lens epithelial-fiber cell differentiation, and the C-terminal domain of Cx45.6 plays a predominant role in mediating this process.Supplementary material available online at

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The carboxy-tail of connexin-43 localizes to the nucleus and inhibits cell growth

Cited by 122 publications

References 10 publications

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

Connexin43 increases the sensitivity of prostate cancer cells to TNFα-induced apoptosis

Promotion of lens epithelial-fiber differentiation by the C-terminus of connexin 45.6 – a role independent of gap junction communication

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