Interferon-induces expression of cyclin-dependent kinase-inhibitors p21WAF1 and p27Kip1 that prevent activation of cyclin-dependent kinase by CDK-activating kinase (CAK)

Mandal, Mahitosh; Bandyopadhyay, Debdutta; Goepfert, Thea M.; Kumar, Rakesh

doi:10.1038/sj.onc.1201529

Cited by 103 publications

(56 citation statements)

References 27 publications

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“…What might be the reason(s) for CKI overexpression in cervical lesions? It has recently been shown that viral infections can induce a general host cell reaction through the action of interferon g, known to activate the p21 WAF1/CIP1 and p27 KIP1 pathway (Mandal et al, 1998). The same study demonstrated that interferon a activates only p21 WAF1/ CIP1 .…”

Section: Discussionmentioning

confidence: 92%

Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

et al. 1999

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High risk types of human papillomavirus (HPV) are agents in the aetiology of cervical carcinoma. The products of two early genes, E6 and E7, appear to be the principal transforming proteins. Studies of various monolayer cell culture systems have shown that the E7 oncoprotein of human papillomavirus type 16 is able to neutralize or bypass the inhibitory e ect of the cell cycledependent kinase (CDK) inhibitors (CKIs) p21 WAF1/CIP1 and p27 KIP1 . To understand whether the p21 WAF1/CIP1 or p27 KIP1 neutralization also plays a role in vivo, we performed studies on clinical specimens. Forty-®ve cervical biopsies, including HPV-negative mucosa, HPV 16-positive preinvasive (low and high grade lesions) and invasive neoplasia as well as HPV 6-positive condyloma acuminatum were analysed by single and double immunohistology. We examined the positive cell cycle regulator cyclin A and the universal cell cycle marker Ki67 as well as the negative cell cycle regulators p21 WAF1/CIP1 and p27 KIP1 . Here, we show that in a signi®cant fraction of cells the G1 block can be overcome despite high levels of CKIs in HPV lesions. This phenomenon, which was more evident for p21 WAF1/CIP1 than for p27 KIP1 was most marked in low grade lesions and in condylomata acuminata, in which a high viral productivity is expected. These results indicate that the overriding of CKI inactivation by viral oncoproteins appears to be a conserved property between low and high risk HPV types. We conclude that the CKI neutralization by HPVs is likely to be required for viral DNA replication rather than for malignant transformation of the host cell.

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Section: Discussionmentioning

confidence: 92%

Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

et al. 1999

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“…The major alterations in cell cycle proteins in response to CSF-1 treatment of MCF-7fms cells were increases in cyclin D1 and p21. p21 has been implicated in the G 1 arrest induced by a variety of agents, including DNA-damaging agents (el-Deiry et al, 1994;Poon et al, 1996), interferons (Mandal et al, 1998), heregulin (Bacus et al, 1996), NGF (Yan and Zi, 1995;Pumiglia and Decker, 1997), FGF (Johnson et al, 1998) and high intensity activation of the Ras/Raf/ MEK/MAPK pathway Sewing et al, 1997;Woods et al, 1997;Lin et al, 1998). Also enforced expression of p21 under an inducible promoter in a variety of cell types has provided additional support for p21 playing a role in inhibiting the G 1 -S transition (Niculescu et al, 1998;Sekiguchi and Hunter, 1998;Bates et al, 1998).…”

Section: Waf1mentioning

confidence: 99%

CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth arrest of hormone-dependent human breast cancer cells

1999

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The CSF-1 receptor (CSF-1R) is expressed in 450% of human breast cancers. To investigate the consequence of CSF-1R expression, hormone-dependent human breast cancer cell lines, MCF-7 and T-47D, were transfected with CSF-1R. Unexpectedly, CSF-1 substantially inhibited estradiol (E 2 ) and insulin-dependent proliferation of MCF-7 transfectants (MCF-7fms) and prevented cyclin E/cdk2 and cyclin A/cdk2 activation, consistent with a G 1 arrest. In contrast, CSF-1 increased DNA synthesis in T-47D transfectants (T-47Dfms) alone and with E 2 or insulin. In response to CSF-1, there was a marked and sustained upregulation of the cyclindependent kinase inhibitor, p21, in MCF-7fms but not T-47Dfms. CSF-1 also markedly upregulated cyclin D1 in MCF-7fms. The coordinate increase in cyclin D1 and p21 had the eect of decreasing the speci®c but not absolute activity of cyclin D1/cdk4. p53 was not involved since CSF-1 induction of p21 was unaected by dominant-negative p53 expression. ERK activation by CSF-1 was robust and sustained in MCF7fms and to a much lesser extent in T-47Dfms. Using pharmacological and transient transfection approaches, we showed that ERK activation was necessary and sucient for p21 induction in MCF-7fms. Moreover, activated MEK inhibited E 2 -stimulated cdk2 activity. Our ®ndings indicate that the consequence of CSF-1R-mediated signals in human breast cancer cells is dependent on the genetic background of the particular tumor.

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“…15 Furthermore, cell cycle progression is regulated by the expression of cyclin-dependent kinase inhibitors (CKIs) such as p27 kip1 and p21 waf , which bind to CDKs and prevent their activation 14,15 Accumulating evidences sustain the notion that transcriptional factors by regulating CDKs and CKIs expression modulate cell cycle progression. 16,17 STAT5 has been reported to regulate the CKI p21 waf expression in different settings 18,19 that include Tie2-mediated and VEGFR1-mediated signals. 11 This observation is consistent with the finding that Tie2 6 -8 and VEGFR1 20 activation did not trigger proliferating signals in ECs.…”

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confidence: 99%

Angiopoietin 2 Induces Cell Cycle Arrest in Endothelial Cells: A Possible Mechanism Involved in Advanced Plaque Neovascularization

Calvi

Dentelli

Pagano

et al. 2004

ATVB

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Objective-To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques. Methods and Results-Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21 waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (⌬STAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions. 3 Consistently, in vivo developing primary lesions might be considered as underperfused and dependent on neovessel formation for continued growth. 4 Angiogenesis in mature tissues is composed of a series of cellular responses including activation of EC proliferation by angiogenic factors, such as VEGF, fibroblast growth factor (FGF), and angiopoietins (Angio) and formation of tube-like structures and vessel stabilization. 5 Compared with the developmental angiogenesis, the role of angiopoietins in pathological angiogenesis is less understood. The angiopoietin family consists of four members, Angio1 to 4. 6 -8 Angio1 and 4 stimulate their receptor tyrosine kinase Tie2, whereas Angio2 and 3 by binding to Tie2 antagonize Angio1 signaling. 6 -8 Signal transduction pathways via Tie2 and VEGF receptors (VEGFR) have been extensively examined. 9,10 In particular, Korpelainem et al showed that Tie2 and VEGFR1 overexpression triggers the phosphorylation of the signal transducer and activator of transcription (STAT) 3 and STAT5. 11 STAT5 belongs to the family of transcriptional factors, which, on activation, binds to the receptor via their src homology 2 domain (SH2). 12 Recruited STATs, dimerize, translocate to the nucleus, and activate transcription of target genes mainly involved in regulation of cell cycle progression. 12,13 Cell cycle phases are coordinated by regulatory proteins denoted as cyclins and cyclin-dependent kinases (CDKs). 14 Phase-specific cyclin/CDK complexes confer specificity and orderly progression through the cell cycle. Initially, cyclin D/CDK4 or cyclin E/CDK2 complexes, in cooperation with proliferating cell nuclear antigen (PCNA), coordinate DNA duplication by regulating the transition through the G1 and S phase. 15 Furthermore, cell cycle progression is ...

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Interferon-induces expression of cyclin-dependent kinase-inhibitors p21WAF1 and p27Kip1 that prevent activation of cyclin-dependent kinase by CDK-activating kinase (CAK)

Cited by 103 publications

References 27 publications

Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth arrest of hormone-dependent human breast cancer cells

Angiopoietin 2 Induces Cell Cycle Arrest in Endothelial Cells: A Possible Mechanism Involved in Advanced Plaque Neovascularization

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