Calmodulin-specific monoclonal antibodies inhibit DNA replication in mammalian cells

Reddy, G. Prem Veer; Reed, W. C.; Sheehan, Erika; Sacks, David B.

doi:10.1021/bi00158a002

Cited by 46 publications

(31 citation statements)

References 41 publications

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“…13 In addition, microinjection of monoclonal antibodies against CaM inhibited the synthesis of DNA in a dose-dependent manner. 14 Moreover, progression through G 1 and mitosis exit was observed to be sensitive to changes in the intracellular concentration of CaM. 15 Other reports specifically supported a role for CaM in the G 1 /S transition.…”

Section: Ca 2+ /Cam Play a Role In Cell Cycle Progressionmentioning

confidence: 98%

Calmodulin-Mediated Cell Cycle Regulation: New Mechanisms for Old Observations

Choi

Husain²

2006

Cell Cycle

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Section: Ca 2+ /Cam Play a Role In Cell Cycle Progressionmentioning

confidence: 98%

Calmodulin-Mediated Cell Cycle Regulation: New Mechanisms for Old Observations

Choi

Husain²

2006

Cell Cycle

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“…Calmodulin is a Ca 2+ binding protein that acts as a Ca 2+ sensor in the cell cycle. High expression of calmodulin has been observed during the S phase and mitosis, while inhibition of its activity by administration of calmodulin monoclonal antibodies is shown to block DNA synthesis [17] . Another sensory mechanism occurs through an extracellular calcium ion concentration sensing receptor (CaR) and calbindin, a high affinity Ca 2+ -binding regulatory protein belonging to the same family as calmodulin.…”

Section: Cyclingmentioning

confidence: 99%

Calcium signaling and T-type calcium channels in cancer cell cycling

Taylor¹,

Zeng²,

Pottle³

et al. 2008

WJG

139

108

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Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca 2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca 2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel is minimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca 2+ channels are not expressed in epithelial cells, selective T-type Ca 2+ channel blockers may be useful in the treatment of certain types of cancers.

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“…chlorpromazine, inhibit electrical uncoupling in Xenopus embryos [14,15] and in epidermal cells [16]. Calmodulin antagonists and antibodies inhibit cell proliferation [17], an effect which may be related to efficacy of gap-junction-mediated communication, since there is increasing evidence that there is a direct correlation between the functional expression of connexins and growth control in cells transfected with connexin genes [18]. Other more direct biochemical approaches have also shown that calmodulin binds to intact gap junctions and tryptic fragments of rat liver connexin 32 in a Ca# + -independent manner [6,19].…”

Section: Introductionmentioning

confidence: 99%

Connexin 32 of gap junctions contains two cytoplasmic calmodulin-binding domains

Török

Stauffer

Evans

1997

Biochemical Journal

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A fluorescent calmodulin derivative, 2-chloro-[4-(ϵ-amino-Lys75)]-[6-(4-diethylaminophenyl)-1,3,5-triazin-4-yl]-calmodulin (TA-calmodulin) [Török and Trentham (1994) Biochemistry 33, 12807–12820], and equilibrium fluorescence methods were used to identify calmodulin-binding domains of connexin subunits of gap junctions. Synthetic peptides corresponding to six extramembrane regions of connexin 32, a major component of rat liver gap junctions, and peptides derived from connexin 43 and 26, were tested. Two cytoplasmically oriented peptides that correspond to an N-terminal 21-amino-acid sequence and a 15-amino-acid sequence at the C-terminal tail of connexin 32 bound TA-calmodulin in a Ca2+-dependent manner. The dissociation constants (Kd) of TA-calmodulin binding to GAP 10 (MNWTGLYTLLSGVNRHSTAIG, residues 1–21) and GAP 8M (ACARRAQRRSNPPSR, residues 216–230) were 27 nM and 1.2 μM respectively at 150 mM ionic strength, 2 mM MgCl2, 100 μM CaCl2, pH 7.0 and 21 °C. Both halves of each peptide were required for calmodulin binding. Substitution of Trp3 present in all connexins by Tyr increasedKd for TA-calmodulin by 40-fold. Liver gap junctions (whose connexons contain mainly connexin 32) and recombinant connexons constructed of connexin 26 expressed by baculovirus-infected insect cells exhibited weaker binding of TA-calmodulin with variable Ca2+-dependence. These studies identify two calmodulin-binding amino-acid sequences in connexin 32, and provide independent evidence that calmodulin may function as an intracellular ligand, regulating Ca2+-dependent intercellular communication across gap junctions.

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Calmodulin-specific monoclonal antibodies inhibit DNA replication in mammalian cells

Cited by 46 publications

References 41 publications

Calmodulin-Mediated Cell Cycle Regulation: New Mechanisms for Old Observations

Calmodulin-Mediated Cell Cycle Regulation: New Mechanisms for Old Observations

Calcium signaling and T-type calcium channels in cancer cell cycling

Connexin 32 of gap junctions contains two cytoplasmic calmodulin-binding domains

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