-
[show abstract]
[hide abstract]
ABSTRACT: The anti-cancer drug doxorubicin is associated with an increased risk of cardiac damage and dysfunction, which can be acute as well as chronic. Fibroblast growth factor 2 (FGF-2) provides cardioprotection from ischemia-reperfusion injury but its effects on doxorubicin-induced damage are not known. We investigated the acute effects of doxorubicin administered in the absence and presence of FGF-2 pre-treatment, on isolated mouse perfused heart function over a period of 120 min. Doxorubicin elicited a significant decrease in left ventricular developed pressure (DP) at 30 min that persisted throughout the study. No effect on lactate dehydrogenase levels was detected in the perfusate, suggesting a lack of significant plasma membrane damage. FGF-2 pre-treatment lessened the deleterious effect of doxorubicin on DP significantly, and this beneficial effect of FGF-2 was blunted by protein kinase C inhibition with chelerythrine. Pre-treatment with a non-mitogenic FGF-2 mutant or FGF-16 also protected against a doxorubicin-induced decrease in DP. FGF-16 as well as FGF-2 pre-treatment elicited a small and transient negative inotropic effect. In conclusion, FGF-2 and FGF-16 increase resistance to acute doxorubicin-induced cardiac dysfunction, and protein kinase C activation is implicated in this response.
Cardiovascular toxicology 02/2013; · 2.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: AIMS: The anti-cancer anthracycline doxorubicin (DOX) increases the risk of cardiac damage, indicating a need to protect the heart and still allow the benefits of drug treatment. Fibroblast growth factor-2 (FGF-2) is cardioprotective against ischemia-reperfusion injury. Our aim is to investigate: (1) the ability of FGF-2 to protect against DOX-induced cardiomyocyte damage, and (2) the contribution of efflux drug transport to any increase in injury-resistance.Methods and ResultsNeonatal rat cardiomyocyte damage was assessed by measuring cell death markers and lactate dehydrogenase (LDH) activity in the culture medium. LDH activity was increased significantly after incubation with 0.5 µM DOX for 24 hours in the absence but not presence of 10 nM FGF-2; this beneficial effect of FGF-2 was blocked by FGF tyrosine kinase receptor inhibition. An increase in efflux drug transporter RNA levels was also detected after FGF-2 treatment in the presence of DOX. The beneficial effect of FGF-2 against cell damage and increased transporter RNA levels were blunted with protein kinase C (PKC) inhibition. Finally, FGF-2 stimulated efflux transport of calcein and DOX, and treatment with efflux transporter inhibitors significantly attenuated the protective effect of FGF-2 from DOX-induced injury.Conclusion(s)Administered FGF-2 increases resistance to DOX-induced cardiomyocyte damage, by a mechanism dependent on PKC as well as regulation of efflux transporter production and/or function.
Cardiovascular research 01/2013; · 5.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Connexin-43 (Cx43) is a membrane phosphoprotein that mediates direct inter-cellular communication by forming gap junctions. In this way Cx43 can influence gene expression, differentiation and growth. Its role in adipogenesis, however, is poorly understood. In this study, we established that Cx43 becomes highly phosphorylated in early adipocyte differentiation and translocates to the plasma membrane from the endoplasmic reticulum. As preadipocytes differentiate, Cx43 phosphorylation declines, the protein is displaced from the plasma membrane, and total cellular levels are reduced via proteosomal degradation. Notably, we show that inhibiting Cx43 degradation or constitutively over-expressing Cx43 blocks adipocyte differentiation. These data reveal that transient activation of Cx43 via phosphorylation followed by its degradation is vital for preadipocyte differentiation and maturation of functional adipocytes.
Biochimica et Biophysica Acta 06/2012; 1823(10):1731-44. · 4.66 Impact Factor
-
Sijo J Thandapilly,
Xavier L Louis,
Tonghua Yang,
Danielle M Stringer,
Liping Yu,
Shetuan Zhang,
Jeffrey Wigle, Elissavet Kardami,
Peter Zahradka,
Carla Taylor,
Hope D Anderson,
Thomas Netticadan
[show abstract]
[hide abstract]
ABSTRACT: Increased adrenergic drive is a major factor influencing the development of pathological cardiac hypertrophy, a stage which precedes overt heart failure. We examined the effect of resveratrol, a polyphenol (found predominantly in grapes), in preventing norepinephrine induced hypertrophy of adult cardiomyocyte, and the role of nitric oxide (NO) and adenosine monophosphate kinase (AMPK) in the effects of resveratrol. Cardiomyocytes isolated from adult rats were pretreated, or not, with resveratrol and then exposed to norepinephrine for 24h. In other experiments cardiomyocytes were also treated with different pharmacological inhibitors of NO synthase, AMPK and sirtuin for elucidating the signaling pathways underlying the effect of resveratrol. In order to validate the role of these signaling molecules in the in vivo settings, we also examined hearts from resveratrol treated spontaneously hypertensive rats (SHR), a genetic model of essential hypertension. Cardiomyocyte hypertrophy was determined by morphometry and (3)H-phenylalanine incorporation assay. NO levels and AMPK activity were measured using a specific assay kit and western blot analysis respectively. In vitro, resveratrol prevented the norepinephrine-induced increase in cardiomyocytes size and protein synthesis. Pharmacological inhibition of NO-AMPK signaling abolished the anti-hypertrophic action of resveratrol. Consistent with the in vitro findings, the anti-hypertrophic effect of resveratrol in the SHR model was associated with increases in NO and AMPK activity. This study demonstrates that NO-AMPK signaling is linked to the anti-hypertrophic effect of resveratrol in adult cardiomyocytes in vitro, and in the SHR model in vivo.
European journal of pharmacology 07/2011; 668(1-2):217-24. · 2.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The fundamental role played by connexins including connexin43 (Cx43) in forming intercellular communication channels (gap junctions), ensuring electrical and metabolic coupling between cells, has long been recognized and extensively investigated. There is also increasing recognition that Cx43, and other connexins, have additional roles, such as the ability to regulate cell proliferation, migration, and cytoprotection. Multiple phosphorylation sites, targets of different signaling pathways, are present at the regulatory, C-terminal domain of Cx43, and contribute to constitutive as well as transient phosphorylation Cx43 patterns, responding to ever-changing environmental stimuli and corresponding cellular needs. The present paper will focus on Cx43 in the heart, and provide an overview of the emerging recognition of a relationship between Cx43, its phosphorylation pattern, and development of resistance to injury. We will also review our recent work regarding the role of an enhanced phosphorylation state of Cx43 in cardioprotection. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.
Biochimica et Biophysica Acta 07/2011; 1818(8):2009-13. · 4.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fibroblast growth factor-2 (FGF-2) is implicated in cardioprotection. However, previously we found that chronic elevation in cardiac FGF-2 levels in transgenic mice was associated with exaggerated, cyclosporine A-preventable, cellular infiltration after isoproterenol-induced injury, suggestive of an adverse outcome, although this was not examined with functional studies. We have now used highly sensitive tissue Doppler imaging (TDI) to evaluate cardiac functional parameters after isoproterenol administration in transgenic mice overexpressing the 18 kDa FGF-2 in the heart in vivo. Cardiac function was assessed in conscious FGF-2 transgenic and non-transgenic mice at 24 h as well as 2 and 4 weeks after isoproterenol administration, and in the absence or presence of either cyclosporine A or anti-CD3ε treatments. Isoproterenol decreased left ventricular endocardial velocity and strain rate by 47-51% at 24 h in non-transgenic mice, but to a significantly lesser extent (by 24%) in transgenic mice. While additional decreases were seen in non-transgenic mice at 2 weeks, there was no further reduction in ventricular endocardial velocity or strain rate up to 4 weeks post-treatment in FGF-2 transgenic mice. Functional improvement at 2 and 4 weeks post-isoproterenol was reduced significantly by treatment with cyclosporine A but not anti-CD3ε; the latter targets T lymphocyte activation more specifically. TDI values in the presence of chronic FGF-2 overexpression are prognostic of an improved cardiac outcome and protection from isoproterenol induced cardiac dysfunction in vivo. Our data also suggest that cyclosporine A-sensitive infiltrating cell population(s) may contribute to the sustained beneficial effect of FGF-2 in vivo.
Molecular and Cellular Biochemistry 05/2011; 357(1-2):1-8. · 2.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have investigated whether acute (swimming) exercise is sufficient to have sustained beneficial effects against cardiac functional decline observed after high-dose isoproterenol administration. Mice were subjected to one bout of swimming for 30 min ("swim" group). Twenty-four hours later, they were given isoproterenol (160 mg/kg) to cause injury. Two control groups were included, a shallow "water" group, for which no swimming took place, and a "cage" group; they were both given isoproterenol as in the "swim" group. Cardiac function was assessed by tissue Doppler imaging (TDI) 24 h, 2 weeks, and 4 weeks post-isoproterenol. Left ventricular (LV) systolic function including endocardial velocity and radial strain rate declined significantly in all groups at all time points after isoproterenol, compared with their pre-isoproterenol treatment values. The "swim" group, however, had significantly higher LV systolic function compared with either of the control groups at 24 h, and this improvement persisted 2 and 4 weeks post-treatment. There were no significant differences between the control groups at any time point. In conclusion, a single bout of swimming has sustained beneficial effects against injury, as measured by TDI, after administration of isoproterenol.
The Journal of Physiological Sciences 04/2011; 61(4):331-6. · 1.61 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although fibroblast growth factor-2 (FGF-2) plays an important role in cardioprotection and growth, little is known about the signals triggered by it in the adult heart. We therefore examined FGF-2-induced effects on phosphoinositide-specific phospholipase C (PI-PLC) isozymes, which produce second messengers linked to the inotropic and hypertrophic response of the myocardium. FGF-2, administered by retrograde perfusion to the isolated heart, induced an increase in inositol-1,4,5-trisphosphate levels in the cytosol, as well as an increase in total PI-PLC activity associated with sarcolemmal and cytosolic fractions. Furthermore FGF-2 induced a time-dependent elevation in cardiomyocyte membrane-associated PLC gamma1 and PLC β1 activities, assayed in immunoprecipitated fractions, and moreover, increased the membrane levels of PLC β1 and PLC β3. Activation of PLC β is suggestive of FGF-2-induced cross-talk between FGF-receptor tyrosine kinase and G-protein-coupled signaling in adult cardiomyocytes and underscores the importance of FGF-2 in cardiac physiology.Key words: FGF-2, signal transduction, PLC gamma, PLC β, cardiomyocytes.
Biochemistry and Cell Biology. 01/2011; 77(6):569-575.
-
[show abstract]
[hide abstract]
ABSTRACT: fibroblast growth factor-2 (FGF-2), implicated in paracrine induction of cardiac hypertrophy, is translated as high molecular weight (Hi-FGF-2) and low molecular weight (Lo-FGF-2) isoforms. Paracrine activities are assigned to Lo-FGF-2, whereas Hi-FGF-2 is presumed to have nuclear functions. In this work, we re-examined the latter presumption by asking whether: cardiac non-myocytes (CNMs) accumulate and export Hi-FGF-2 in response to pro-hypertrophic [angiotensin II (Ang II)] stimuli; an unconventional secretory pathway requiring activated caspase-1 affects Hi-FGF2 export; and secreted Hi-FGF-2 is pro-hypertrophic.
using neonatal rat heart-derived cultures and immunoblotting, we show that CNMs accumulated over 90% Hi-FGF-2, at levels at least five-fold higher than cardiomyocytes (CMs). Pro-hypertrophic agents (Ang II, endothelin-1, and isoproterenol) up-regulated CNM-associated Hi-FGF-2. The Ang II effect was mediated by Ang II receptor-1 but not Ang II receptor-2 as it was blocked by losartan but not PD123319. CNM-derived Hi-FGF-2 was detected in two extracellular pools: in conditioned medium from Ang II-stimulated CNMs and in association with the cell surface/matrix, eluted with a gentle 2 M NaCl wash of the cell monolayer. Conditioned medium from Ang II-treated CNMs increased neonatal CM size, an effect prevented by anti-FGF-2-neutralizing antibodies. The caspase-1 inhibitor YVAD prevented the Ang II-induced release of Hi-FGF-2 to both extracellular pools.
CNMs are major producers of Hi-FGF-2, up-regulated by hypertrophic stimuli and exported to the extracellular environment by a mechanism requiring caspase-1 activity, suggesting a link to the innate immune response. Hi-FGF-2 is likely to promote paracrine induction of myocyte hypertrophy in vivo.
Cardiovascular research 01/2011; 89(1):139-47. · 5.80 Impact Factor
-
Roien Ahmadie,
Jon-Jon Santiago,
Jonathan Walker,
Tielan Fang,
Khuong Le,
Zhaohui Zhao,
Nazila Azordegan,
Sheri Bage,
Matthew Lytwyn,
Sunil Rattan,
Ian M C Dixon, Elissavet Kardami,
Mohammed H Moghadasian,
Davinder S Jassal
[show abstract]
[hide abstract]
ABSTRACT: A high-lipid diet (HLD) may lead to adverse left ventricular (LV) remodeling and endothelial dysfunction in conditions of hemodynamic stress. Although congenital absence of nitric oxide synthase 3 (NOS3) leads to adverse LV remodeling after transverse aortic constriction (TAC), the effects of a HLD in this state remains unknown. Wild-type (WT) and NOS3 knockout mice (NOS3(-/-)) were randomized into the following 4 groups: 1) WT + low-lipid diet (LLD) (10% of energy); 2) WT + HLD (60% of energy); 3) NOS3(-/-) + LLD; and 4) NOS3(-/-) + HLD for a total of 12 wk. After 1 wk of randomization, TAC was performed on all groups. Serial echocardiography revealed a decrease in LV ejection fraction (LVEF) in WT and NOS3(-/-) mice fed the HLD compared with those fed the LLD diet at 12 wk post-TAC. Mice fed the NOS3(-/-) + HLD diet had a lower LVEF compared with mice in the other 3 groups (P < 0.05). There was greater myocyte hypertrophy, interstitial fibrosis, and percentage change in plasma cholesterol concentrations in the NOS3(-/-) + HLD group 12 wk post-TAC compared with the other 3 groups. Although high molecular weight fibroblast growth factor-2, a marker of cardiac hypertrophy, was more upregulated in the NOS3(-/-) + HLD group than in the other groups, markers of the renin-angiotensin system did not differ among them. A HLD potentiates LV dysfunction in NOS3(-/-) mice in a chronic pressure overload state.
Journal of Nutrition 08/2010; 140(8):1438-44. · 3.92 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In fibrosing hearts, myofibroblasts are associated with cardiac extracellular matrix remodeling. Expression of key genes in the transition of cardiac fibroblast to myofibroblast phenotype in post-myocardial infarction heart and in vitro has not been well addressed. Contractile, focal adhesion-associated, receptor proteins, fibroblast growth factor-2 (FGF-2) expression, and motility were compared to assess phenotype in adult and neonatal rat cardiac fibroblasts and myofibroblasts. Neonatal and adult fibroblasts undergo phenotypic transition to myofibroblastic cells, marked by increased alpha-smooth muscle actin (alphaSMA), smooth muscle myosin heavy chain (SMemb), extra domain-A (ED-A) fibronectin, paxillin, tensin, FGF-2, and TbetaRII receptor. Elevated ED-A fibronectin confirmed fibroblast to supermature myofibroblastic phenotype transition. Presence of myofibroblasts in vivo was noted in sections of healed infarct scar after myocardial infarction, and their expression is similar to that in culture. Thus, cultured neonatal and adult cardiac fibroblasts transition to myofibroblasts in vitro and share expression profiles of cardiac myofibroblasts in vivo. Reduced motility with in vitro passage reflects enhanced production of focal adhesions.
Developmental Dynamics 06/2010; 239(6):1573-84. · 2.54 Impact Factor
-
Canadian Journal of Physiology and Pharmacology 01/2010; 88(1):82. · 1.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fibroblast growth factor 2 (FGF-2) is a multifunctional protein translated as high and low molecular weight isoforms (hi- and lo-FGF-2, respectively). Although the postconditioning cardioprotective effect of lo-FGF-2 (18 kDa) has been documented, hi-FGF-2 is less well studied. We used an isolated perfused rat heart model of ischemia-reperfusion to study the effects of postischemic (during reperfusion) administration of hi-FGF-2 on recovery of contractile function and tissue salvage, as indicated by decreased cytosolic cytochrome c levels. Compared with the vehicle-treated group, hi-FGF-2-treated hearts had significantly improved recovery of systolic pressure, developed pressure, rates of contraction and relaxation, and coronary flow, as well as decreased relative levels of cytosolic cytochrome c. The effects of hi-FGF-2 on functional recovery and cytosolic cytochrome c were indistinguishable from those induced by lo-FGF-2. Both hi- and lo-FGF-2 upregulated relative levels of phosphorylated (activated) Akt and p70 S6 kinase, and they both promoted translocation of alpha, epsilon, and zeta isoforms of protein kinase C (PKC) to the particulate fraction of reperfused hearts. The magnitude of the effect on PKCzeta and p70 S6 kinases, however, was significantly more potent in the hi-FGF-2 than in the lo-FGF-2 group. We conclude that acute postischemic cardioprotection by hi- or lo-FGF-2 is isoform nonspecific and likely to be mediated by PKC and Akt. Nevertheless, isoform-specific functions are suggested by the augmented sensitivity of p70 S6 and PKCzeta to hi-FGF-2.
Canadian Journal of Physiology and Pharmacology 10/2009; 87(10):798-804. · 1.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The cardioprotective agent fibroblast growth factor 2 (FGF-2) was found previously to promote phosphorylation of connexin-43 (Cx43) at protein kinase C (PKC) sites such as serine (S) 262 at levels above those of non-stimulated hearts. We asked if other PKC-dependent cardioprotective treatments cause a similar effect, and if Cx43 phosphorylation at S262 mediates resistance to injury.
Isolated perfused adult rat hearts were subjected to the following treatments: ischaemic preconditioning (PC); diazoxide perfusion; FGF-2 pre-treatment followed by 30 min global ischaemia; 30 min global ischaemia followed by 60 min reperfusion in the presence or absence of FGF-2. Cx43 phosphorylation was assessed by western blotting with phospho-specific antibodies. Neonatal cardiomyocyte cultures were used to examine the effect of expressing Cx43 incapable of being phosphorylated at S262 due to an S to alanine (A) substitution on simulated ischaemia-induced cell death (TUNEL staining) and injury (lactic dehydrogenase release). Ischaemic PC, diazoxide, and FGF-2 pre-ischaemic or post-ischaemic treatments elicited a P Cx43 state, defined as above-physiological levels of phospho-S262-Cx43 and phospho-S368-Cx43. P Cx43 was sustained during global ischaemia and was accompanied by attenuation of ischaemia-induced Cx43 dephosphorylation and prevention of Cx43 lateralization. Post-ischaemic FGF-2 treatment also diminished dephosphorylated Cx43. Modest overexpression of S262A-Cx43, but not wild-type Cx43, exacerbated cardiomyocyte death and injury caused by simulated ischaemia in vitro. It also prevented the cytoprotective effects of FGF-2 or overexpressed PKCepsilon.
P Cx43 marks a state of enhanced resistance to ischaemic injury promoted by PKC-activating treatments such as FGF-2 administration or ischaemic PC. Cx43 phosphorylation at S262 likely mediates PKCepsilon-dependent cardioprotection.
Cardiovascular research 06/2009; 83(4):672-81. · 5.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Boosting myocardial resistance to acute as well as chronic ischemic damage would ameliorate the detrimental effects of numerous cardiac pathologies and reduce the probability of transition to heart failure. Experimental cardiology has pointed to ischemic and pharmacological pre- as well as post-conditioning as potent acute cardioprotective manipulations. Additional exciting experimental strategies include the induction of true regenerative and/or angiogenic responses to the damaged heart, resulting in sustained structural and functional beneficial effects. Fibroblast growth factor-2 (FGF-2), an endogenous multifunctional protein with strong affinity for the extracellular matrix and basal lamina and well-documented paracrine, autocrine and intracellular modes of action, has been shown over the years to exert acute and direct pro-survival effects, irrespectively of whether it is administered before, during or after an ischemic insult to the heart. FGF-2 is also a potent angiogenic protein and a crucial agent for the proliferation, expansion, and survival of several cell types including those with stem cell properties. Human clinical trials have pointed to a good safety record for this protein. In this review, we will present a case for the low molecular weight isoform of fibroblast growth factor-2 (lo-FGF-2) as a very promising therapeutic agent to achieve powerful acute as well as sustained benefits for the heart, due to its cytoprotective and regenerative properties.
Heart Failure Reviews 01/2008; 12(3-4):267-77. · 3.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fibroblast growth factor 2 (FGF-2) is produced as CUG-initiated, 22-34 kDa or AUG-initiated 18 kDa isoforms (hi- and lo-FGF-2, respectively), with potentially distinct functions. We report that expression of hi-FGF-2 in HEK293 cells elicited chromatin compaction preceding cell death with apoptotic features. Nuclear localization of the intact protein was required as expression of a non-nuclear hi-FGF-2 mutant failed to elicit chromatin compaction. Equally ineffective, despite nuclear localization, was the over-expression of the 18 kDa core sequence (lo-FGF-2). Chromatin compaction by hi-FGF-2 was accompanied by increased cytosolic cytochrome C, and was attenuated either by over-expression of Bcl-2 or by a peptide inhibitor of the pro-apoptotic protein Bax. In addition hi-FGF-2 elicited sustained activation of total and nuclear extracellular signal regulated kinase (ERK1/2) by an intracrine route, as it was not prevented by neutralizing anti-FGF-2 antibodies. Inhibition of the ERK1/2 activating pathway by dominant negative upstream activating kinase, or by PD 98059, prevented chromatin compaction by hi-FGF-2. ERK1/2 activation was not affected by the Bax-inhibiting peptide suggesting that it occurred upstream of mitochondrial involvement. We conclude that the hi-FGF-2-induced chromatin compaction and cell death requires its nuclear localization, intracrine ERK1/2 activation and mitochondrial engagement.
Journal of Cellular Physiology 01/2008; 213(3):690-8. · 3.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The heart expresses high and low molecular weight (hmw, lmw) fibroblast growth factor 2 (FGF-2) isoforms. While the injury-repair-related activities of lmw-FGF-2 have been studied extensively, those of hmw-FGF-2 have not. Thus, we investigated the effects of hmw-FGF-2 on acute as well as chronic responses to myocardial infarction (MI) induced by irreversible coronary occlusion in the rat. Hmw- or lmw-FGF-2 was injected into the ischemic zone during acute evolving MI. Both isoforms were equally effective in reducing infarct size (at 24 h post-MI) and improving heart function up to 6 weeks post-MI, compared to a vehicle-treated infarcted group. Lmw-FGF-2 alone upregulated vascularization in the infarct. Hmw-FGF-2 elicited significant hypertrophy, compared to the vehicle-treated group, at 4-8 weeks post-MI, assessed by ultrasound, heart morphometry and cardiomyocyte cross-sectional area. In addition, hmw- (but not lmw-) FGF-2-treated hearts displayed increased accumulation of the cytokine cardiotrophin-1 and its signal transducer gp130. In culture, hmw- (but not lmw-) FGF-2 increased cardiomyocyte protein synthesis and cell size as well as upregulated cardiotrophin-1 released by cardiac fibroblasts, pointing to similar activities in vivo. Thus, hmw- and lmw-FGF-2 exert isoform-specific effects in the heart and only hmw-FGF-2 triggers cardiomyocyte hypertrophic growth. Direct effects of hmw-FGF-2 on cardiomyocytes, becoming reinforced and sustained by upregulation of cardiotrophin-1 and acting in concert with other factors, are likely to contribute to post-MI hypertrophy.
Journal of Molecular and Cellular Cardiology 02/2007; 42(1):222-33. · 5.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this paper is to provide a brief overview of current thinking on the role of connexins, in particular Cx43, in growth regulation, and a more detailed discussion as to potential mechanisms involved with an emphasis on gene expression. While the precise molecular mechanism by which connexins can affect the growth of normal or tumor cells remains elusive, a number of exciting reports have expanded our understanding and are presented in some detail. Thus, we will discuss (Section 2): the role of protein-protein interactions in integrating connexins into multiple signal transduction pathways; phosphorylation at specific sites and reversal of growth inhibition; the role of the carboxy-terminal regulatory domain as a signaling molecule. Some of our latest work on the potential functions of endogenously produced carboxy-terminal fragments of Cx43 are also presented (Section 3). Finally, Section 4 will pay tribute to the rapidly emerging realization that connexins such as Cx43 and Cx32 exert important and extensive effects on gene expression, particularly those genes linked to growth regulation.
Progress in Biophysics and Molecular Biology 01/2007; 94(1-2):245-64. · 3.20 Impact Factor
-
Annals of the New York Academy of Sciences 12/2006; 752(1):353 - 369. · 3.15 Impact Factor
-
Annals of the New York Academy of Sciences 12/2006; 638(1):244 - 255. · 3.15 Impact Factor
