Calcium, cyclic AMP and protein kinase C ? partners in mitogenesis

Whitfield, J. F.; Durkin, Jon P.; Franks, Douglas J.; Kleine, Leonard P.; Raptis, Leda; Rixon, R. H.; Sikorska, Marianna; Walker, P. Roy

doi:10.1007/bf00046999

Cited by 82 publications

(27 citation statements)

References 376 publications

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“…IP, is known to release Ca++ from intracellular stores, leading to the activation of several proteins and enzymes, among them, a calcium-receptor protein, calmodulin (CaM). While the involvement of protein kinase C and cyclic nucleotides (CAMP and cGMP) in cellular proliferation is widely implicated [Whitfield et al, 1987;Persons et al, 19881, their causal relationship to and their specific mechanism of action in the growth factor-dependent transition of cells from GI to S phase are controversial [Besterman et al, 1986;Jacob and Cuatrecasas, 19861. Cyclin-dependent protein kinases (CDKs) have emerged in recent years as key regulators of cell cycle progression both in yeast and in mamma- lian cells [Lee et al, 19881. In addition to the changes in cyclin levels, as shown in Figure 3, the activation of CDKs and their interaction with cyclins are associated with the ability of cells to progress from one phase to the next [Pines and Hunter, 1990;Sherr, 19931.…”

Section: Metabolic Events Associated With the Progression Of Cells Frmentioning

confidence: 99%

Cell cycle: Regulatory events in G₁ → S transition of mammalian cells

Reddy

1994

J of Cellular Biochemistry

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A cell divides into two daughter cells by progressing serially through the precisely controlled G1, S, GZ, and M phases of the cell cycle. The crossing of the G1/S border, which is marked by the initiation of DNA synthesis, represents commitment to division into two complete cells. Beyond this critical point no further external signals are required. We now have more comprehensive knowledge of the temporal sequence of systems at this key transition from G1 to S-growth factor responses, a cascade of kinase reactions, activation of cyclins and their associated kinases, and oncogene and tumor suppressor gene products. Furthermore, we know that the absolute requirement for calcium and the timing of events associated with calmodulin and the 68 kDa calmodulin-binding protein are consistent with overall Ca++/calmodulin control of all steps from the response to growth factors in G1 to DNA replication in S phase. We now have to sort out the inter-relationships of myriad control proteins and their relation to the Ca++/calmodulin-dependent controls-Which are causes? Which are effects? And which are parallel processes? The answers will be important, as they represent both a much deeper understanding of this key process of life and an important opportunity for improving therapeutic medicine.

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Section: Metabolic Events Associated With the Progression Of Cells Frmentioning

confidence: 99%

Cell cycle: Regulatory events in G₁ → S transition of mammalian cells

Reddy

1994

J of Cellular Biochemistry

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“…Cyclic AMP (cAMP) is a significant regulator of normal liver regeneration and in vitro hepatocyte proliferation (Boynton and Whitfield, 1983;Brønstad et al 1983;Friedman et al 1981;Whitfield et al 1987). Norepinephrine, glucagon, and vasopressin all appear to participate in the regulation of liver replication or related functions through this pathway (Michalopoulos, 1991).…”

Section: Introductionmentioning

confidence: 98%

Localization of cAMP-dependent signal transducers in early rat liver carcinogenesis

Skarpen

Taskén

et al. 1998

Histochemistry and Cell Biology

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Cyclic AMP (cAMP) is an important regulator of liver growth and differentiation. The main intracellular cAMP receptor, cAMP-dependent protein kinase (PKA), consists of two regulatory (R) and two catalytic (C) subunits. There are two classes, RI and RII, of the regulatory subunit, giving rise to type I (RI2C2) and type II (RII2C2) PKA. The RI/RII ratio generally decreases during organ development, and increases during carcinogenesis. Alterations in this ratio have been implicated as an important factor in experimental and clinical carcinogenesis. We have studied the expression of RIalpha, RIIalpha, Calpha, and an important substrate of PKA, the cAMP-response element binding protein, during rat liver carcinogenesis. Two-color immunofluorescence and confocal laser scan microscopy were used to characterize localization of the cAMP-dependent signal transducers in hepatocytes, bile ducts, oval cells, and preneoplastic lesions. We found that bile ducts and oval cells (putative liver stem cells) contained a higher RI/RII ratio than hepatocytes and preneoplastic lesions. Thus, an altered RI/RII ratio was not detected during early rat liver carcinogenesis, but may contribute to differentiation of putative liver stem cells to hepatocytes.

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“…tissue-type and urokinase-type plasminogen activators [34-], metalloproteinases [35,36], and tissue inhibitors of metalloproteinases (TIMPs) [37,38]. Furthermore, the contention that pH and Ca 2+ affect invasive behavior is circumstantially supported by the ability of kinase C to stimulate invasive behavior in a wide variety of tumor cells [39][40][41][42][43][44]. Activation of kinase C often leads to an increased pH in [45][46][47][48][49][50].…”

Section: Introductionmentioning

confidence: 99%

Acidic pH enhances the invasive behavior of human melanoma cells

et al. 1996

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As a consequence of poor perfusion and elevated acid production, the extracellular pH (pHex) of tumors is generally acidic. Despite this, most in vitro experiments are still performed at the relatively alkaline pHex of 7.4. This is significant, because slight changes in pHex can have profound effects on cell phenotype. In this study we examined the effects of mildly acidic conditions on the in vitro invasive potential of two human melanoma cell lines; the highly invasive C8161, and poorly invasive A375P. We observed that culturing of either cell line at acidic pH (6.8) caused dramatic increases in both migration and invasion, as measured with the Membrane Invasion Culture System (MICS). This was not due to a direct effect of pH on the invasive machinery, since cells cultured at normal pH (7.4) and tested at acidic pH did not exhibit increased invasive potential. Similarly, cells cultured at acidic pH were more aggressive than control cells when tested at the same medium pH. These data indicate that culturing of cells at mildly acidic pH induces them to become more invasive. Since acid pH will affect the intracellular pH (pHin) and intracellular calcium ([Ca2+]in), we examined the effect of these parameters on invasion. While changes in [Ca2+]in were not consistent with invasive potential, the changes in pHin were. While these conditions decrease the overall amount of gelatinases A and B secreted by these cells, there is a consistent and significant increase in the proportion of the activated form of gelatinase B.

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Calcium, cyclic AMP and protein kinase C ? partners in mitogenesis

Cited by 82 publications

References 376 publications

Cell cycle: Regulatory events in G₁ → S transition of mammalian cells

Cell cycle: Regulatory events in G₁ → S transition of mammalian cells

Localization of cAMP-dependent signal transducers in early rat liver carcinogenesis

Acidic pH enhances the invasive behavior of human melanoma cells

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Calcium, cyclic AMP and protein kinase C ? partners in mitogenesis

Cited by 82 publications

References 376 publications

Cell cycle: Regulatory events in G1 → S transition of mammalian cells

Cell cycle: Regulatory events in G1 → S transition of mammalian cells

Localization of cAMP-dependent signal transducers in early rat liver carcinogenesis

Acidic pH enhances the invasive behavior of human melanoma cells

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Cell cycle: Regulatory events in G₁ → S transition of mammalian cells

Cell cycle: Regulatory events in G₁ → S transition of mammalian cells