Implication of CDK Inhibitors p21 and p27 in the Differentiation of HL-60 Cells

Horie, Nobutaka; Mori, Tsuyoshi; Asada, Hidetsugu; Ishikawa, Aki; Johnston, Patrick G.; Takeishi, Keiichi

doi:10.1248/bpb.27.992

Cited by 11 publications

(10 citation statements)

References 19 publications

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“…In this case the potent antiproliferative activity of PIN was associated with the p53-independent overexpression of the CDK inhibitor p21 WAF1/Cip1 , to the inhibition of G1 to S cell cycle transition and to the induction of differentiation. The causal role played by p21 WAF1/Cip1 in the cell cycle progression and terminal differentiation of HL60 cells has been widely studied and demonstrated (37,38). Therefore, our results provide the first evidence suggesting that PIN may exert its effects on proliferation and differentiation mainly though the up-regulation of p21 WAF1/Cip1 .…”

Section: Discussionsupporting

confidence: 61%

Pinoresinol Inhibits Proliferation and Induces Differentiation on Human HL60 Leukemia Cells

Sepporta

Mazza

Morozzi

et al. 2013

Nutrition and Cancer

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Pinoresinol (PIN), one of the simplest lignans, is the precursor of other dietary lignans that are present in whole-grain cereals, legumes, fruits, and other vegetables. Several experimental and epidemiological evidences suggest that lignans may prevent human cancer in different organs. In this study we investigated the chemopreventive properties of PIN on cell lines derived from different sites either expressing or not the functional tumor suppressor protein p53. It was found that PIN inhibited the proliferation of p53 wild type colon and prostate tumor cells (HCT116 and LNCaP) while in breast cells the inhibition of growth was observed only in p53 mutant cells (MDA-MB-231). A potent antiproliferative activity of PIN was also observed on p53 null cells HL60 (IC50% 8 μM), their multidrug resistant variant HL60R (IC50% 32 μM) and K562. On HL60 cells, PIN caused a block of cell cycle in the G0/G1 phase, induced a weak proapoptotic effect but it was a good trigger of differentiation (NBT reduction and CD11b expression). PIN caused an upregulation of the CDK inhibitor p21(WAF1/Cip1) both at mRNA and protein levels so suggesting that this could be a mechanism by which PIN reduced proliferation and induced differentiation on HL60 cells.

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Section: Discussionsupporting

confidence: 61%

Pinoresinol Inhibits Proliferation and Induces Differentiation on Human HL60 Leukemia Cells

Sepporta

Mazza

Morozzi

et al. 2013

Nutrition and Cancer

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“…Even though the molecular mechanisms by which Bis induces growth retardation in HL-60 cells is not clear, an elevated expression of p27 in HL-60-bis cells provide a possibility that p27 functions as a mediator that delays the cell cycle progression. Our presumption is supported by a recent paper showing that HL-60 cells expressing antisense RNA for p27 revealed a significant decrease in their ability to differentiate into granulocytes (Horie et al, 2004), indicating that an increased expression of p27 is essential for cellular differentiation of HL-60 cells. However, differentiation was shown to be uncoupled from growth arrest in several cells such as primary keratinocytes or luteal cells.…”

Section: Discussionsupporting

confidence: 81%

Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27

Seo

Jeon²,

Lee³

et al. 2005

Exp Mol Med

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Bis (Bag-3, CAIR), a Bcl-2-interacting protein, promotes the anti-apoptotic activity of Bcl-2 and increased levels of Bis have been observed in several disease models. The involvement of Bcl-2 and some Bcl-2-binding proteins in differentiation has recently been reported. However, the relevance of Bis to cellular differentiation remains unknown. The findings herein show that Bis expression is up-regulated during the differentiation of HL-60 cells. To investigate the effect of Bis expression on differentiation, we established Bis-overexpressing HL-60 cells (HL-60-bis). HL-60-bis cells have a low nuclear: cytoplasmic ratio and indented nucleus in WrightGiemsa staining, and an increased expression of CD11b in immunofluorescence study, indicating the promotion of differentiation. The overexpression of Bis also resulted in a retarded cell growth rate, accompanied by the accumulation of HL-60 cells at the G0/G1 phase of the cell cycle, which was sustained during the differentiation process. Western blot analysis revealed that the expression of p27, a representative inducer of cell cycle arrest at the G1 phase, was increased 2.5-fold in HL-60-bis cells compared to HL-60-neo cells. These results suggest that the Bis induced growth inhibition of HL-60 cells promotes G0/G1 phase arrest via up-regulation of p27, which seems to be a prerequisite for differentiation. Further studies will be required to define the exact roles of Bis on cellular differentiation more precisely.

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“…The p27Kip1 cyclin dependent kinase inhibitor (CDKI) plays a key role in determining the onset of the S-phase [43]. ATRA induced p27Kip1 expression consistent with the G1/G0 cell cycle arrest known to occur [44] and adding roscovitine slightly enhanced this ( Figure 6A). p27Kip1 is known to target the cyclin E1/Cdk2 complex.…”

Section: Roscovitine Enhances Atra-induced Changes In Certain Canonicmentioning

confidence: 78%

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

et al. 2020

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Although ATRA represents a successful differentiation therapy for APL, it is largely ineffective for non-APL AMLs. Hence combination therapies using an agent targeting ATRA-regulated molecules that drive cell differentiation/arrest are of interest. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation/G0-arrest, we now observe that roscovitine enhanced nuclear enrichment of certain traditionally cytoplasmic signaling molecules and enhanced differentiation and cell cycle arrest. Roscovitine upregulated ATRA-induced nuclear c-Raf phosphorylation at S259 and S289/296/301. Nuclear c-Raf interacted with RB protein and specifically with pS608RB, the hinge region phosphorylation controlling E2F binding and cell cycle progression. ATRA-induced loss of pS608RB with cell cycle arrest was associated with loss of RB-sequestered c-Raf, thereby coupling cell cycle arrest and increased availability of c-Raf to promote differentiation. Part of this mechanism reflects promoting cell cycle arrest via ATRAinduced upregulation of the p27 Kip1 CDKI. Roscovitine also enhanced the ATRAinduced nuclear enrichment of other signaling molecules traditionally perceived as cytoplasmic promoters of proliferation, but now known to promote differentiation; in particular: SFKs, Lyn, Fgr; adaptor proteins, c-Cbl, SLP-76; a guanine exchange factor, Vav1; and a transcription factor, IRF-1. Akin to c-Raf, Lyn bound to RB, specifically to pS608RB. Lyn-pS608RB association was greatly diminished by ATRA and essentially lost in ATRA plus roscovitine treated cells. Interestingly Lyn-KD enhanced such ATRAinduced nuclear signaling and differentiation and made roscovitine more effective. ATRA thus mobilized traditionally cytoplasmic signaling molecules to the nucleus where they drove differentiation which were further enhanced by roscovitine.

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Implication of CDK Inhibitors p21 and p27 in the Differentiation of HL-60 Cells

Cited by 11 publications

References 19 publications

Pinoresinol Inhibits Proliferation and Induces Differentiation on Human HL60 Leukemia Cells

Pinoresinol Inhibits Proliferation and Induces Differentiation on Human HL60 Leukemia Cells

Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

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