Inhibitors of Calcineurin Block Expression of Cyclins A and E Induced by Fibroblast Growth Factor in Swiss 3T3 Fibroblasts

Tomono, Masahiro; Toyoshima, Kotaro; Ito, Motohiro; Amano, Hisao; Kiss, Zoltán

doi:10.1006/abbi.1998.0667

Cited by 47 publications

(37 citation statements)

References 34 publications

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“…However, the progression through the cell cycle is regulated by several cyclins. CCE, as opposed to NCCE, activates calcineurin (Mignen et al, 2003), which in turn allows expression of cyclin A and E (Tomono et al, 1998), and cyclin D2 induction is abolished in the presence of CCE blockers (Glassford et al, 2003). Therefore, it is likely that calcium influx may block cell proliferation by preventing cyclin induction.…”

Section: Discussionmentioning

confidence: 99%

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

Mignen

Brink

Enfissi

et al. 2005

Journal of Cell Science

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Blocking calcium entry may prevent normal and pathological cell proliferation. There is evidence suggesting that molecules such as carboxyamidotriazole, widely used in anti-cancer therapy based on its ability to block calcium entry in nonexcitable cells, also have antiproliferative properties. We found that carboxyamidotriazole and the capacitative calcium entry blocker 2-aminoethoxydiphenyl borate inhibited proliferation in HEK-293 cells with IC50 values of 1.6 and 50 μM, respectively. Capacitative calcium entry is activated as a result of intracellular calcium store depletion. However, non-capacitative calcium entry pathways exist that are independent of store depletion and are activated by arachidonic acid and diacylglycerol, generated subsequent to G protein coupled receptor stimulation. We found that carboxyamidotriazole completely inhibited the capacitative calcium entry and had no effect on the amplitude of arachidonic-acid-activated non-capacitative calcium entry. However, investigation of the effects of carboxyamidotriazole on mitochondrial calcium dynamics induced by carbachol, capacitative calcium entry and exogenously set calcium loads in intact and digitonin-permeabilized cells revealed that carboxyamidotriazole inhibited both calcium entry and mitochondrial calcium uptake in a time-dependent manner. Mitochondrial inner-membrane potential was altered by carboxyamidotriazole treatment, suggesting that carboxyamidotriazole antagonizes mitochondrial calcium import and thus local calcium clearance, which is crucial for the maintenance of capacitative calcium entry.

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Section: Discussionmentioning

confidence: 99%

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

Mignen

Brink

Enfissi

et al. 2005

Journal of Cell Science

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“…In mammals, calcineurin mediates T cell and B cell proliferation (15,24,25,36) and has been implicated in urotensin II-mediated proliferation of airway SMC (7), angiotensin II-induced cardiac fibroblast hyperplasia (12), and pituitary cell proliferation (11). Indeed, calcineurin has been shown to be essential for DNA synthesis in Swiss 3T3 fibroblasts (47), where inhibitors of calcineurin block the fibroblast growth factor-mediated expression of cyclins A and E (48).…”

Section: Discussionmentioning

confidence: 99%

“…Both c-Myb and calcineurin influence Ca 2ϩ -mediated signals of cell cycle (1,22,47,48 influx and a c-Myb-dependent reduction in Ca 2ϩ efflux mediated via repression of PMCA1 (1,22,23,40,41). Indeed, ϳ60% of the c-Myb effect on VSMC proliferation is exerted via PMCA1 repression (22).…”

Section: Discussionmentioning

confidence: 99%

Calcineurin-independent regulation of plasma membrane Ca²⁺ ATPase-4 in the vascular smooth muscle cell cycle

Afroze

Yang

Wang

et al. 2003

American Journal of Physiology-Cell Physiology

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. Calcineurinindependent regulation of plasma membrane Ca 2ϩ ATPase-4 in the vascular smooth muscle cell cycle. Am J Physiol Cell Physiol 285: C88-C95, 2003; 10.1152/ajpcell.00518.2002.-Calcineurin mediates repression of plasma membrane Ca 2ϩ -ATPase-4 (PMCA4) expression in neurons, whereas c-Myb is known to repress PMCA1 expression in vascular smooth muscle cells (VSMC). Here, we describe a novel mouse VSMC line (MOVAS) in which 45 Ca efflux rates decreased 50%, fura 2-AM-based intracellular Ca 2ϩ concentrations ([Ca 2ϩ ]i) increased twofold, and real-time RT-PCR and Western blot revealed a ϳ40% decrease in PMCA4 expression levels from G 0 to G1/S in the cell cycle, where PMCA4 constituted ϳ20% of total PMCA protein. Although calcineurin activity increased fivefold as MOVAS progressed from G0 to G1/S, inhibition of this increase with either BAPTA or retroviral transduction with peptide inhibitors of calcineurin (CAIN), or its downstream target nuclear factor of activated T cells (NFAT) (VIVIT), had no effect on the repression of PMCA4 mRNA expression at G1/S. By contrast, Ca 2ϩ -independent activity of the calmodulin-dependent protein kinase-II (CaMK-II) increased eightfold as MOVAS progressed from G0 to G1/S, and treatment with an inhibitor of CaMK-II (KN-93) or transduction of a c-Myb-neutralizing antibody significantly alleviated the G1/S-associated repression of PMCA4. These data show that G1/S-specific PMCA4 repression in proliferating VSMC is brought about by c-Myb and CaMK-II and that calcineurin may regulate cell cycle-associated [Ca 2ϩ ]i through alternate targets. /calmodulin-mediated signals act at multiple points in the cell cycle, including the G 0 /G 1 transition, the initiation of S-phase, and the initiation and completion of M phase (reviewed in Refs. 4,31,38,and 44 ] i ) needed for G 1 -to-S transitions in rat vascular smooth muscle cells (VSMC) (22, 23).We previously showed that the cell cycle-associated repression of PMCA1 expression during G 0 to G 1 /S progression in rat VSMC is mediated by the c-Myb transcription factor (1). However, the mechanism(s) underlying the cell cycle-associated repression of PMCA4 had not been elucidated. Guerini et al. (18) demonstrated in mouse neurons that PMCA4 expression can be repressed by a calcineurin-dependent pathway. Given this result, we hypothesized that G 1 /Sassociated repression of PMCA4 expression in VSMC may also be mediated by calcineurin. To explore these mechanisms in cell culture, we generated a clonal, immortalized mouse VSMC line (MOVAS). Immunostaining for smooth muscle-specific proteins such as SM22␣, calponin, smooth muscle-specific ␣-actin and desmin, as well as SM22␣ promoter-driven enhanced green fluorescent protein (EGFP) expression, confirm the lineage and phenotype of these cells. 45 Ca efflux assays and fura 2-based ratiometric Ca 2ϩ imaging reveal regulated Ca 2ϩ efflux and [Ca 2ϩ ] i at the G 1 /S transition point. Western blot and real time RT-PCR reveal cell cycle-regulated repression of mouse PMCA1 and PMCA4. Drugs in...

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“…Of special interest in this context is the role of Ca 2+ /calcineurin/NFAT signaling in cell cycle control, since calcium signaling has been shown to promote cell cycle progression and G 1 /S phase transition in a variety of normal cells [37][38][39] as well as transformed cells. 40 Moreover, it has been demonstrated that overexpression of a constitutively active NFATc1 mutant is sufficient to induce a transformed phenotype in preadipocyte 3T3-L1 fibroblasts, associated with altered expression of cell-cycle related genes such as cyclin D1, cyclin D2, pRB and, most notably, c-myc.…”

Section: Oncogenic Potential Of Nfat Signalingmentioning

confidence: 99%

An Emerging Role for Ca2+/Calcineurin/NFAT Signaling in Cancerogenesis

Buchholz

Ellenrieder²

2007

Cell Cycle

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Inhibitors of Calcineurin Block Expression of Cyclins A and E Induced by Fibroblast Growth Factor in Swiss 3T3 Fibroblasts

Cited by 47 publications

References 34 publications

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

Calcineurin-independent regulation of plasma membrane Ca²⁺ ATPase-4 in the vascular smooth muscle cell cycle

An Emerging Role for Ca2+/Calcineurin/NFAT Signaling in Cancerogenesis

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Inhibitors of Calcineurin Block Expression of Cyclins A and E Induced by Fibroblast Growth Factor in Swiss 3T3 Fibroblasts

Cited by 47 publications

References 34 publications

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

Calcineurin-independent regulation of plasma membrane Ca2+ ATPase-4 in the vascular smooth muscle cell cycle

An Emerging Role for Ca2+/Calcineurin/NFAT Signaling in Cancerogenesis

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Calcineurin-independent regulation of plasma membrane Ca²⁺ ATPase-4 in the vascular smooth muscle cell cycle