Unexpected Induction of the Human Connexin 43 Promoter by the Ras Signaling Pathway Is Mediated by a Novel Putative Promoter Sequence

Carystinos, George D.; Kandouz, Mustapha; Alaoui‐Jamali, Moulay A.; Batist, Gerald

doi:10.1124/mol.63.4.821

Cited by 56 publications

(46 citation statements)

References 81 publications

(89 reference statements)

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“…Since we have shown that the ERK1/2 pathway is the principal conduit for other bFGF effects in BSMC (14), the present findings reconfirm its importance in functional bladder remodeling. These findings are also in accordance with a report that connexin 43 expression is mediated by MAPK pathways in other kinds of cells (4,16). Additionally, connexin 43 was hardly observed in BSMC in the absence of bFGF but was markedly expressed in BSMC in the presence of bFGF (Figs.…”

Section: Discussionsupporting

confidence: 82%

Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle

Imamura¹,

Negoro²,

Kanematsu³

et al. 2009

American Journal of Physiology-Renal Physiology

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Overactive bladder is a highly prevalent clinical condition that is often caused by bladder outlet obstruction (BOO). Increased coupling of bladder smooth muscle cells (BSMC) via gap junctions has been hypothesized as a mechanism for myogenic bladder overactivity in BOO, although little is known about the regulatory system underlying such changes. Here, we report the involvement of basic fibroblast growth factor (bFGF) and connexin 43, a bladder gap junction protein, in bladder overactivity. BOO created by urethral constriction in rats resulted in elevated bFGF and connexin 43 levels in the bladder urothelium and muscle layer, respectively, and muscle strips from these bladders were more sensitive than those from sham-operated controls to a cholinergic agonist. In vitro bFGF treatment increased connexin 43 expression in cultured rat BSMC via the ERK 1/2 pathway. This finding was supported by another in vivo model, where bFGF released from gelatin hydrogels fixed on rat bladder walls caused connexin 43 upregulation and gap junction formation in the muscle layer. Bladder muscle strips in this model showed increased sensitivity to a cholinergic agonist that was blocked by inhibition of gap junction function with α-glycyrrhetinic acid. Cystometric analyses of this model showed typical features of detrusor overactivity such as significantly increased micturition frequency and decreased bladder capacity. These findings suggest that bFGF from the urothelium could induce bladder hypersensitivity to acetylcholine via gap junction generation in the smooth muscle, thereby contributing to the myogenic overactivity of obstructed bladders.

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Section: Discussionsupporting

confidence: 82%

Basic fibroblast growth factor causes urinary bladder overactivity through gap junction generation in the smooth muscle

Imamura¹,

Negoro²,

Kanematsu³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…The cell response to 4-PBA is complex and includes changes in gene expression and inhibition of histone acetylation (Chen et al 1997;Wright et al 2004), which can also affect Cx43 expression Asklund et al 2004;Hattori et al 2007;Khan et al 2007). Interestingly, geldanamycin, an agent also shown to alter Cx43 regulation (Carystinos et al 2003;Lidington et al 2000Lidington et al , 2002Rodriguez-Sinovas et al 2006) had no effect on 3(3) cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of rab20 as a Potential Regulator of Connexin43 Trafficking

Sarma

Kaplan

Willemsen

et al. 2008

Cell Communication & Adhesion

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Connexin oligomerization and trafficking are regulated processes. To identify proteins that control connexin43 (Cx43), a screen was designed using HeLa cells expressing a Cx43 construct with di-lysine endoplasmic reticulum (ER)-retention/retrieval motif, Cx43-HKKSL. At moderate levels of expression, Cx43-HKKSL is retained in the ER as monomers; however, Cx43-HKKSL stably overexpressed by HeLa cells localizes to the perinuclear region and oligomerizes. HeLa/Cx43-HKKSL overexpressors were transiently transfected with pooled clones from a human kidney cDNA library and used immunofluorescence microscopy to identify cDNAs that enabled overexpressed Cx43-HKKSL to convert from a perinuclear to ER localization pattern. Using this approach, a small molecular weight GTPase, rab20, was identified as a candidate protein with the ability to regulate Cx43 trafficking. Enhanced green florescent protein (EGFP)-tagged rab20 showed a predominantly perinuclear and ER localization pattern and caused wild-type Cx43 to be retained inside the cell. By contrast, mutant EGFP-rab20T19N, which lacks the ability to bind GTP, had no effect on Cx43. These results suggest Cx43 is transported through an intracellular compartment regulated by rab20 along the secretory pathway.

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“…Several genes in the opn network are involved in apoptosis including, Mac-2 antigen (Lgals3), ryanodine receptor (Ryr2), Cardiac troponin T (Tnnt2) and Connexin 43 (Gja1). Connexin 43 (Gja1) is essential for cell survival and tightly regulated at the transcriptional and post-transcriptional levels (Carystinos et al, 2003). Kcnk3 is a potassium channel subfamily K (TASK) member.…”

Section: Resultsmentioning

confidence: 99%