Retinoblastoma protein-overexpressing HL60 cells resistant to 1,25-dihydroxyvitamin D3 display increased CDK2 and CDK6 activity and shortened G1 phase

Wang, Qing Mei; Luo, Xun; Kheir, Ahmed; Coffman, Frederick D.; Studzinski, George P.

doi:10.1038/sj.onc.1201803

Cited by 19 publications

(17 citation statements)

References 27 publications

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“…3 a). CDK4 and CDK6 are, however, not functionally redundant and are differentially regulated by mitogenic signals (Laliberte et al, 1998 ;Wang et al, 1997Wang et al, , 1998. The pronounced restriction of both the catalytic and regulatory subunits of CDK4 and CDK6 complexes found in UV-MV-treated PBL might be sufficient to explain their reduced activity in vitro (Fig.…”

Section: Discussionmentioning

confidence: 99%

Measles virus-induced immunosuppression in vitro is associated with deregulation of G1 cell cycle control proteins.

Engelking

Fedorov

Lilischkis

et al. 1999

Journal of General Virology

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Virus-induced immunosuppression is the major cause of the high morbidity/mortality rates associated with acute measles. It has been shown previously that mitogen-dependent proliferation of peripheral blood lymphocytes (PBL) was strongly impaired after contact with the measles virus (MV) glycoproteins F and H expressed on the surface of infected cells, cells transfected with the corresponding expression constructs or UV-inactivated MV (UV-MV). The state of unresponsiveness was not associated with the induction of apoptosis, and a significant proportion of PBL was found to be arrested in the G 0 /G 1 phase of the cell cycle. It is now shown that cell cycle cessation, rather than complete arrest, is induced after MV glycoprotein contact. No obvious role was found for p53 in the induction of this unresponsiveness. With UV-MV as effector, downregulation of p27, an inhibitor of cyclin-dependent kinase (CDK)-cyclin complexes, was significantly delayed after mitogenic stimulation of human PBL. The activities of both CDK4/6-cyclin D and CDK2-cyclin E complexes for phosphorylation of exogenous substrates in vitro were strongly reduced. CDK4, CDK6, cyclins D3 and E and, to a minor extent, CDK2 failed to accumulate at the protein level after mitogenic stimulation in the presence of UV-MV. These data indicate that MV-induced proliferative unresponsiveness of PBL to mitogenic stimulation is associated with a drastic deregulation of the expression of cell cycle genes essential for the G 1 /S phase transition.

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Section: Discussionmentioning

confidence: 99%

Measles virus-induced immunosuppression in vitro is associated with deregulation of G1 cell cycle control proteins.

Engelking

Fedorov

Lilischkis

et al. 1999

Journal of General Virology

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“…[17][18][19]23 Expression of the markers of differentiation, on the other hand, showed little if any relationship to the levels of p27…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] These data, and additional studies of other cell cycle regulatory proteins, 23 indicate that a marked up-regulation of p27 Kip1 , with its subsequent attenuation upon resumption of cell growth, is characteristic of p27…”

Section: Long-term Exposure Attenuates the 125d 3 -Induced Elevationmentioning

confidence: 99%

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Lowering of p27Kip1 levels by its antisense or by development of resistance to 1,25-dihydroxyvitamin D3 reverses the G1 block but not differentiation of HL60 cells

Qm¹,

Chen²,

Luo³

et al. 1998

Leukemia

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Cyclin-dependent kinase inhibitors are proteins with functions which appear to involve regulation of cell cycle traverse, and have been suggested to have a role in cell differentiation. However, there is as yet no rigorous proof that this is the case. We have addressed the participation of one of these inhibitors, p27Kip1 , in the induction of differentiation and the subsequent G1 block induced in HL60 cells by 1,25-dihydroxyvitamin D 3 (1,25D 3 ). First, it was noted that sublines of HL60 cells able to grow rapidly in the presence of 1,25D 3 have protein levels of p27Kip1 lower than the levels in cells subjected to 1,25D 3 -induced growth inhibition, but higher than in untreated parental cells. In contrast, there was no discernible relationship between the levels of p27Kip1 and the expression of differentiation markers. Further, HL60 cells treated with 1,25D 3 and an oligonucleotide antisense, but not mismatched, to p27 Kip1showed an almost complete elimination of the 1,25D 3 -induced G1 block, but no decrease in the expression of differentiation markers. Similar results were obtained following transient transfection with an expression vector bearing the entire p27Kip1 coding sequence in the anti-sense orientation. This is the first direct demonstration that p27Kip1 plays a role in the 1,25D 3 -induced G1 arrest, and that partial reduction in its levels has no effect on the induction of differentiation in HL60 cells.

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“…Previous results have indicated that the levels of p27 Kip1 were decreased, whereas those of cyclin D1, D2, D3, and E were elevated, in HL60 cells resistant to 1,25-dihydroxyvitamin D3 when compared with sensitive cells. 37,38 Accordingly, our HL60AR cells are resistant to ATRA 16 and displayed lower levels of p27 Kip1 and a higher amount of cyclin D1 when compared with ATRA-sensitive (PT) cells.…”

Section: Figurementioning

confidence: 99%

The phosphoinositide 3-kinase/Akt pathway regulates cell cycle progression of HL60 human leukemia cells through cytoplasmic relocalization of the cyclin-dependent kinase inhibitor p27Kip1 and control of cyclin D1 expression

et al. 2003

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The serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K), plays a pivotal role in tumorigenesis because it affects the growth and survival of cancer cells. Several laboratories have demonstrated that Akt inhibits transcriptional activation of a number of related forkhead transcription factors now referred to as FoxO1, FoxO3, and FoxO4. Akt-regulated forkhead transcription factors are involved in the control of the expression of both the cyclindependent kinase (cdk) inhibitor p27 Kip1 and proapoptotic Bim protein. Very little information is available concerning the importance of the PI3K/Akt pathway in HL60 human leukemia cells. Here, we present our findings showing that the PI3K/Akt axis regulates cell cycle progression of HL60 cells through multiple mechanisms also involving the control of FoxO1 and FoxO3. To this end, we took advantage of a HL60 cell clone (HL60AR cells) with a constitutively activated PI3K/Akt axis. When compared with parental (PT) HL60 cells, HL60AR cells displayed higher levels of phosphorylated FoxO1 and FoxO3. In AR cells forkhead factors localized predominantly in the cytoplasm, whereas in PT cells they were mostly nuclear. AR cells proliferated faster than PT cells and showed a lower amount of the cdk inhibitor p27 Kip1 , which was mainly found in the cytoplasm and was hyperphosphorylated on threonine residues. AR cells also displayed higher levels of cyclin D1 and phosphorylated p110 Retinoblastoma protein. The protein levels of cdk2, cdk4, and cdk6 were not altered in HL60AR cells, whereas the activities of both ckd2 and cdk6 were higher in AR than in PT cells. These results show that in HL60 cells the PI3K/Akt signaling pathway may be involved in the control of the cell cycle progression most likely through mechanisms involving the activation of forkhead transcription factors.

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Retinoblastoma protein-overexpressing HL60 cells resistant to 1,25-dihydroxyvitamin D3 display increased CDK2 and CDK6 activity and shortened G1 phase

Cited by 19 publications

References 27 publications

Measles virus-induced immunosuppression in vitro is associated with deregulation of G1 cell cycle control proteins.

Measles virus-induced immunosuppression in vitro is associated with deregulation of G1 cell cycle control proteins.

Lowering of p27Kip1 levels by its antisense or by development of resistance to 1,25-dihydroxyvitamin D3 reverses the G1 block but not differentiation of HL60 cells

The phosphoinositide 3-kinase/Akt pathway regulates cell cycle progression of HL60 human leukemia cells through cytoplasmic relocalization of the cyclin-dependent kinase inhibitor p27Kip1 and control of cyclin D1 expression

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