UCN-01-Induced Cell Cycle Arrest Requires the Transcriptional Induction of p21waf1/cip1 by Activation of Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase Pathway

Facchinetti, María Marta; Siervi, Adriana De; Toskos, Doreen; Senderowicz, Adrian M.

doi:10.1158/0008-5472.can-03-3741

Cited by 49 publications

(39 citation statements)

References 57 publications

(67 reference statements)

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“…p21 Cip1 up-regulation in HeLa and SKOV-3 cells in response to growth factors, oxidative stress, or PMA is dependent upon the ERK MAPK cascade (10,51,52). Regulation of p21 Cip1 via ERK may involve transcriptional or post-transcriptional mechanisms that extend p21 Cip1 half-life (26,53). Pharmacological inhibition of MEK blocks the senescence phenotype triggered by the diterpene PEP005 in melanoma cells (41).…”

Section: Discussionmentioning

confidence: 99%

S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

Oliva

Caino

Senderowicz

et al. 2008

Journal of Biological Chemistry

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Protein kinase C (PKC) has been widely implicated in positive and negative control of cell proliferation. We have recently shown that treatment of non-small cell lung cancer (NSCLC) cells with phorbol 12-myristate 13-acetate (PMA) during G 1 phase inhibits the progression into S phase, an effect mediated by PKC␦-induced up-regulation of the cell cycle inhibitor p21 Cip1 . However, PMA treatment in asynchronously growing NSCLC cells leads to accumulation of cells in G 2 /M. Studies in post-G 1 phases revealed that PMA induced an irreversible G 2 /M cell cycle arrest in NSCLC cells and conferred morphological and biochemical features of senescence, including elevated SA-␤-Gal activity and reduced telomerase activity. Remarkably, this effect was phase-specific, as it occurred only when PKC was activated in S, but not in G 1 , phase. Mechanistic analysis revealed a crucial role for the classical PKC␣ isozyme as mediator of the G 2 /M arrest and senescence, as well as for inducing p21 Cip1 an obligatory event for conferring the senescence phenotype. In addition to the unappreciated role of PKC isozymes, and specifically PKC␣, in senescence, our data introduce the paradigm that discrete PKCs trigger distinctive responses when activated in different phases of the cell cycle via a common mechanism that involves p21 Cip1 up-regulation.Activation of protein kinase C (PKC) 4 with phorbol esters and related natural compounds causes an array of effects on differentiation, mitogenesis, survival, apoptosis, and transformation. The diverse effects of phorbol esters both in normal and cancerous cells is due to the existence of numerous intracellular effectors, of which PKC isozymes have been the most widely characterized. The PKC family comprises 3 subfamilies that include 10 structurally related phospholipid-dependent serine/threonine kinases (1, 2). Members of the classical cPKC (␣, ␤I, ␤II, and ␥) and the novel nPKC (␦, ⑀, , and ) subfamilies are activated by phorbol esters and their cellular analogue, the second messenger diacylglycerol, which leads to redistribution (translocation) of the enzymes from cytosol to intracellular membrane compartments, where they phosphorylate specific substrates. The marked heterogeneity in the signaling events and cell type-specific responses triggered by phorbol esters could be explained by the distinctive pattern of expression and intracellular localization of PKC isozymes and their substrates, which ultimately results in selective pathway activation.One of the paradigms that best exemplifies the functional versatility of PKC isozymes is the regulation of the cell cycle machinery. It became evident in the last years that PKCs can impact on the cell cycle both in positive and negative manners with a strict degree of cell type and isozyme specificity. PKC isozymes have been shown to regulate the progression of cells from G 1 to S phase as well as with the transition from G 2 to M phase (3) via transcriptional, translational, and post-translational mechanisms. PKCs control the activity of cyc...

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Section: Discussionmentioning

confidence: 99%

S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

Oliva

Caino

Senderowicz

et al. 2008

Journal of Biological Chemistry

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“…The cdk inhibitors include the CIP/KIP and INK family of proteins (21 -23). Several cdk inhibitors have been shown to have a role in the regulation of G 1 -S progression (22,30). The cdk inhibitors function by binding to cyclin D-cdk complexes to inhibit their kinase activity.…”

Section: Discussionmentioning

confidence: 99%

“…Wild-type p53 is a transcription factor whose halflife increases after DNA damage (19 -21). As a result, p53 transcriptionally activates the WAF1/p21 promoter, resulting in increase in WAF1/p21 protein levels (21,22). WAF1/ p21 also forms complexes with G 1 cyclin-cdks and inhibits their kinase activity (23).…”

Section: Introductionmentioning

confidence: 99%

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Shukla

Gupta

2006

Molecular Cancer Therapeutics

111

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Apigenin (4V ,5,7-trihydroxyflavone) is a promising chemopreventive agent abundantly present in fruits and vegetables that has been shown to promote cell cycle arrest and apoptosis in various malignant cell lines. To determine whether pharmacologic intervention with apigenin has a direct growth inhibitory effect on human prostate tumors implanted in athymic nude mice, we examined cell cycle regulatory molecules as precise molecular targets of apigenin action. Apigenin feeding by gavage to these mice at doses of 20 and 50 Mg/mouse/d in 0.2 mL of a vehicle containing 0.5% methyl cellulose and 0.025% Tween 20 resulted in significant decreases in tumor volume and mass of androgen-sensitive 22Rv1 and androgen-insensitive PC-3-implanted cells. Oral intake of apigenin resulted in dose-dependent (a) increase in the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18; (b) down-modulation of the protein expression of cyclins D1, D2, and E; and cyclin-dependent kinases (cdk), cdk2, cdk4, and cdk6; (c) decrease in retinoblastoma phosphorylation at serine 780; (d) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27; and (e) decrease in the binding of cyclin E toward cdk2 in both types of tumors. In addition, apigenin feeding resulted in stabilization of p53 by phosphorylation at serine 15 in 22Rv1 tumors, which seems to exhibit p53-dependent growth inhibitory responses. Apigenin intake by these mice also resulted in induction of apoptosis, which positively correlated with serum and tumor apigenin levels. Taken together, this is the first systematic in vivo study showing the involvement of cell cycle regulatory proteins as potential molecular targets of apigenin. [Mol Cancer Ther 2006;5(4):843 -52]

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“…Therefore, p27 levels may be induced by mechanisms that inhibit p27 degradation, such as that observed with proteasome inhibitors MG132 and lovastatin (Lee and Goldberg, 1998;Rao et al, 1999), or following downregulation of Skp2 by siRNA (Jiang et al, 2005). There are scant reports to suggest that p21 may also increase p27 levels (Liu et al, 2000;Steinman et al, 2001;Munoz-Alonso et al, 2005), but other studies contradict this, as no increases in p27 were demonstrated when p21 was induced either ectopically (Yamamoto et al, 1999) or following treatment with UCN-01 (Facchinetti et al, 2004).…”

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confidence: 99%

Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21

Kuang

Huang

et al. 2006

Br J Cancer

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The cisplatin analogue 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum IV (DAP) is a DNA-damaging agent that will be entering clinical trials for its potent cytotoxic effects against cisplatin-resistant tumour cells. This cytotoxicity may reside in its ability to selectively activate G1-phase checkpoint response by inhibiting CDKs via the p53/p21 pathway. We have now evaluated the role of another CDK inhibitor p27 as a contributor to DAP-mediated inhibition of G1-phase CDK2 activity. Our studies in ovarian A2780 tumour cells demonstrate that p27 levels induced by DAP are comparable to or greater than those seen for p21. The induction of p27 is not through a transcriptional mechanism, but rather is due to a four-fold increase in protein stabilisation through a mechanism dependent on p21. Moreover, DAP-induced p21 promoted the selective increase of p27 in the CDK2 complex, but not in CDK4 complex, and this selective increase contributed to inhibition of the CDK2 kinase activity. The inhibited complex contained either p27 or p21, but not both, with the relative levels of cyclin E associated with p27 and p21 indicating that about 25% of the inhibition of CDK2 activity was due to p27 and 75% due to p21. This study provides the first evidence that p27 upregulation is directly attributable to activation of the p53/p21 pathway by a DNA-damaging agent, and promulgates p53/p21/p27 axis as a significant component of checkpoint response.

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UCN-01-Induced Cell Cycle Arrest Requires the Transcriptional Induction of p21waf1/cip1 by Activation of Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase Pathway

Cited by 49 publications

References 57 publications

S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

S-Phase-specific Activation of PKCα Induces Senescence in Non-small Cell Lung Cancer Cells

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Upregulation of p27 and its inhibition of CDK2/cyclin E activity following DNA damage by a novel platinum agent are dependent on the expression of p21

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