Differential control of cyclins D1 and D3 and the cdk inhibitor p27Kip1 by diverse signalling pathways in Swiss 3T3 cells

Mann, David J.; Higgins, Theresa; Jones, Nicholas; Rozengurt, Enrique

doi:10.1038/sj.onc.1201134

Cited by 47 publications

(29 citation statements)

References 30 publications

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“…These observations suggest that intracellular cAMP can mediate the proliferation of thyroid cells by altering the balance between cyclin/CDK complexes and their inhibitors. cAMP-mediated increases in cyclin levels and concomitant decreases in p27 levels have also been reported in granulosa cells (Robker and Richards, 1998) and the mouse ®broblast cell line, Swiss 3T3 (Mann et al, 1997). Recent evidence suggests that the stability of p27 is dictated by its relative molar concentration with cyclin/CDK complexes.…”

Section: Discussionmentioning

confidence: 71%

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

et al. 2000

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p27 Kip1 (p27) controls cell cycle progression by binding to and inhibiting the activity of cyclin dependent kinases. Disruption of the p27 gene in mice (p277/7) results in increased body growth with a disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary. The increase in pituitary size is due to selective hyperplasia of the intermediate lobe (IL) while the anterior lobe (AL) is not overtly a ected. p27 heterozygous mice (p27+/7), as well as p277/7 mice, are hypersensitive to radiation-and chemical-induced tumors compared to wildtype (p27+/+) littermates. Therefore, unlike classical tumor suppressors, only a reduction in p27 levels is necessary to predispose tissues to secondary tumor promoters. Consistent with these studies is the fact that the p27 gene sequence and mRNA levels appear normal in human pituitary adenomas while p27 protein levels are decreased. Therefore, a reduction in p27 levels could be su cient to sensitize pituitary cells to tumorigenic factors. To test this hypothesis, metallothionein promoter-driven, human growth hormone-releasing hormone (MT-hGHRH) transgenic mice, that exhibit somatotrope hyperplasia before 9 months of age and subsequent adenoma formation with 30 ± 40% penetrance, were crossbred with p27+/7 mice for two successive generations to produce p27+/+, p27+/7 and p277/7 mice that expressed the hGHRH transgene. At 10 ± 12 weeks of age, p277/7 and p27+/+, hGHRH mice were larger than their p27+/+ littermates and displayed characteristic hyperplasia of the IL and AL, respectively. Expression of the hGHRH transgene in both p27+/7 and p277/7 mice selectively expanded the population of somatotropes within the AL, where pituitaries of p27+/7, hGHRH and p277/7, hGHRH mice were two-and ®vefold larger than p27+/+, hGHRH pituitaries, respectively. There was also a synergistic e ect of hGHRH transgene expression and p27-de®ciency on liver, spleen and ovarian growth. At 6 ± 8 months of age, 83% of p27+/7, hGHRH mice displayed macroscopic AL adenomas (4100 mg), while all pituitaries from p27+/+, hGHRH mice remained hyperplastic (520 mg). In contrast to the dramatic e ects of p27-de®ciency on hGHRH-induced organ growth, elimination of p53, by crossbreeding MT-hGHRH mice to p53-de®cient mice, did not augment the hyperplastic/ tumorigenic e ects of hGHRH transgene expression.Taken together these results demonstrate that a reduction in p27 expression is su cient to sensitize somatotropes to the proliferative actions of excess GHRH, resulting in the earlier appearance and increased penetrance of hGHRH-induced pituitary tumors.

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Section: Discussionmentioning

confidence: 71%

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

et al. 2000

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“…In PDGF/PPP depndent BA1Bc 3T3 cells, PDGF addition alone abrogates p27 synthesis but is not sucient for progression to S phase. Instead, p27 downregulation in this cell type is a ®rst step in the induction of G0-G1 transition (Agrawal et al, 1996;Mann et al, 1997). A role for p27 in maintaining cells in G0 has been also suggested by suppression of the mitogen-sensitive G0 arrest observed in ®broblasts upon expression of an antisense p27 cDNA (Rivard et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of the cyclin-dependent kinase inhibitor P27 in primary hepatocytes in early-mid G1 and G1/S transitions

et al. 1999

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P27, an inhibitor of cyclin-dependent kinases, plays an important role in the control of cell adhesion and contact inhibition-dependent cell cycle regulation. Hepatocytes, maintained in primary culture, oer a model of synchronized primary epithelial cells which retain a dierentiated pro®le while stimulated to proliferate. We therefore investigated the pattern of endogenous p27 expression in cyclin rat hepatocytes isolated by collagenase perfusion followed by mitogenic stimulation. P27 was expressed in whole normal liver and freshly isolated hepatocytes. We then observed a sharp decrease in p27 levels, concomitant with the progression in earlymid G1, followed by reaccumulation in late G1 and the G1/S transition. Immunochemistry and BrdU labelling demonstrated nuclear localization of p27 and its expression in cells engaged in both G1 and S phase. P27 was detected in late G1 in complexes containing cyclins D1, E and A. Cyclin E-and A-associated kinase activities, however, were detected at the G1/S transition and depletion experiments con®rmed that most active complexes were free of p27. Phosphorylated forms of p27 were detected in unstimulated and stimulated hepatocytes in both early-mid G1 and G1/S. Finally, two-dimensional gel electrophoresis showed evidence for several forms of p27 with a distinct pro®le of distribution in quiescent and stimulated hepatocytes. Collectively, our data oer a model in which p27 shows a biphasic pro®le of accumulation, with the early decrease possibly involved in the progression through early and mid G1. In contrast with most cell types tested so far, the late G1 accumulation did not impair formation of active cyclin E-and A associated kinases, and thus G1/S transition.

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“…The bombesin/gastrin-releasing peptide GPCR also interacts with members of the G 12 family leading to Rho-dependent actin remodeling and tyrosine phosphorylation of focal adhesion proteins, including FAK (10 -17). Subsequently, bombesin induces striking activation of serine phosphorylation cascades (11)(12)(13)(14) and promotes increased expression of immediate early response genes, stimulation of DNA synthesis, and cell proliferation (15)(16)(17)(18)(19). The mechanism(s) linking the early signaling pathways to the subsequent stimulation of cell proliferation remains incompletely understood.…”

mentioning

confidence: 99%

Protein Kinase D Potentiates DNA Synthesis Induced by Gq-coupled Receptors by Increasing the Duration of ERK Signaling in Swiss 3T3 Cells

Sinnett‐Smith

Zhukova

Hsieh

et al. 2004

Journal of Biological Chemistry

108

115

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Neuropeptides are implicated as growth factors in a variety of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation (1-3). In particular, bombesin and its mammalian counterpart gastrin-releasing peptide bind to a GPCR 1 (4, 5) that promotes G␣ q -mediated activation of ␤ isoforms of phospholipase C (6 -8) to produce 2 s messengers: Ins(1,4,5)P 3 that mobilizes Ca 2ϩ from internal stores and diacylglycerol that activates conventional (␣, ␤ 1 , ␤ 2 , and ␥) and novel (␦, ⑀, , and ) PKCs (9, 10). The bombesin/gastrin-releasing peptide GPCR also interacts with members of the G 12 family leading to Rho-dependent actin remodeling and tyrosine phosphorylation of focal adhesion proteins, including FAK (10 -17). Subsequently, bombesin induces striking activation of serine phosphorylation cascades (11)(12)(13)(14) and promotes increased expression of immediate early response genes, stimulation of DNA synthesis, and cell proliferation (15-19). The mechanism(s) linking the early signaling pathways to the subsequent stimulation of cell proliferation remains incompletely understood.PKD (also initially known as PKC) is a serine/threonine protein kinase with structural, enzymology, and regulatory properties different from the PKC family members (20, 21). PKD most distinct characteristics are the presence of a catalytic domain distantly related to Ca 2ϩ -regulated kinases, a pleckstrin homology (PH) region that regulates enzyme activity and a highly hydrophobic stretch of amino acids in its Nterminal region (22)(23)(24). This N-terminal region also contains a tandem repeat of cysteine-rich, zinc finger-like motifs, which confers high affinity for phorbol esters and plays a negative role in the regulation of catalytic kinase activity (25-28). The identification of PKD-2 and PKD-3, similar in overall structure, primary amino acid sequence, and enzymology properties to PKD/PKC (29 -32), supports the notion that PKD isoenzymes constitute a separate family of serine protein kinases.PKD can be activated in intact cells through multiple G protein pathways, including G q , G i , and G 12 (33-39), as well as by biologically active phorbol esters, growth factors and antigen-receptor engagement (36, 37, 39 -45). In all these cases, rapid PKD activation is mediated by PKC-dependent phosphorylation of Ser-744 and Ser-748 within the activation loop of the catalytic domain of PKD (33, 46 -48). PKD activation is associated with its translocation to the plasma membrane and subsequent transient accumulation in the nucleus (25,28,50,51). These findings revealed that PKD is activated by multiple growth-promoting factors (22, 52) suggesting that it functions in mitogenic signaling. Indeed, we reported that PKD overexpression markedly potentiates DNA synthesis induced by the GPCR agonists bombesin and vasopressin in Swiss 3T3 cells (53), a cell line that has been used extensively as a model system to elucidate signal transduction pathways in the mitogenic action of GPCR agonists (1,54,55). Thes...

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Differential control of cyclins D1 and D3 and the cdk inhibitor p27Kip1 by diverse signalling pathways in Swiss 3T3 cells

Cited by 47 publications

References 30 publications

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

Differential expression of the cyclin-dependent kinase inhibitor P27 in primary hepatocytes in early-mid G1 and G1/S transitions

Protein Kinase D Potentiates DNA Synthesis Induced by Gq-coupled Receptors by Increasing the Duration of ERK Signaling in Swiss 3T3 Cells

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