p27 and Leukemia: Cell Cycle and Beyond

Roy, Anita; Banerjee, Subrata

doi:10.1002/jcp.24819

Cited by 55 publications

(35 citation statements)

References 130 publications

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“…However, annexin V/DAPI assay measured at day 4 and day 7 demonstrated that ZNF521 knockdown did not caused increased apoptosis (Figure 2D), suggesting that ZNF521 may be involved in proliferation and differentiation of MLL -rearranged cells rather than in cell survival. To substantiate this hypothesis, GFP-sorted transduced THP-1 and ML-2 cells were collected on glass slides by cytospin and stained with antibodies against p21 (CDKN1A) and p27 (CDKN1B) cell cycle inhibitors [22]. At day 7, we observed an increase of both p21 and p27 protein expression in ZNF521 knockdown cells, suggesting a prolonged G1/S transition as the main reason for the aforementioned cell cycle arrest (Supplementary Figure 3).…”

Section: Resultsmentioning

confidence: 89%

ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia

et al. 2017

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Zinc finger protein 521 (ZNF521) is a multiple zinc finger transcription factor and a strong candidate as regulator of hematopoietic stem cell homeostasis. Recently, independent gene expression profile studies have evidenced a positive correlation between ZNF521 mRNA overexpression and MLL-rearranged acute myeloid leukemia (AML), leaving open the question on the role of ZNF521 in this subtype of leukemia. In this study, we sought to analyze the effect of ZNF521 depletion on MLL-rearranged AML cell lines and MLL-AF9 xenograft primary cells. Knockdown of ZNF521 with short-hairpin RNA (shRNA) led to decreased leukemia proliferation, reduced colony formation and caused cell cycle arrest in MLL-rearranged AML cell lines. Importantly, we showed that loss of ZNF521 substantially caused differentiation of both MLL-rearranged cell lines and primary cells. Moreover, gene profile analysis in ZNF521-silenced THP-1 cells revealed a loss of MLL-AF9-directed leukemic signature and an increase of the differentiation program. Finally, we determined that both MLL-AF9 and MLL-ENL fusion proteins directly interacted with ZNF521 promoter activating its transcription. In conclusion, our findings identify ZNF521 as a critical effector of MLL fusion proteins in blocking myeloid differentiation and highlight ZNF521 as a potential therapeutic target for this subtype of leukemia.

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Section: Resultsmentioning

confidence: 89%

ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia

et al. 2017

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“…Furthermore, we showed in vivo and in vitro that the rescuing effect of antibody blockade and SIS3 treatment was accompanied by suppression of p27 and enhancement of CDK2- cyclin E activities. It is well known that p27 is a CDK inhibitor, forming quaternary complexes with CDKs and thereby preventing cell cycle progression via cell-cycle arrest at the G1 phase 30 . Like CRP, TGF-β1 can also induce p27 protein expression while inhibiting CDK2 and cyclin E. 20–22, 31 In the present study using ChIP assays we showed that Smad3, a key member of the TGF-β signaling family of molecules, was capable of binding to the p27 promoter in response to CRP stimulation.…”

Section: Discussionmentioning

confidence: 99%

C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E

Lai

Tang

Huang

et al. 2016

Kidney International

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Previous studies have shown that acute kidney injury (AKI) is exacerbated in C-reactive protein transgenic mice (CRP Tg) and alleviated in Smad3 knockout mice (Smad3 KO). The present study used CRP Tg, Smad3 KO, and CRP Tg/Smad3 KO mice to investigate the signaling mechanisms by which CRP promotes AKI. As previously reported, we found that the elevation of serum creatinine and the extent of tubular epithelial cell (TEC) necrosis following ischemia-reperfusion injury (IRI) induced AKI was greater for CRP Tg than wild type (Wt). In contrast in Smad3 KO mice, whether CRP Wt or CRP Tg, these responses were blunted. Exacerbation of AKI in CRP Tg was associated with increased TGF-β/Smad3 signaling, i.e. increased expression of the cyclin kinase inhibitor p27, suppression of phosphorylated CDK2, and decreased expression of cyclin E. Concomitantly, TEC proliferation was arrested at the G1 phase in CRP Tg, as evidenced by fewer BrdU+ and PCNA+ cells. On the other hand protection from AKI in Smad3 KO mice was associated with decreased expression of p27 and promotion of CDK2/cyclin E-dependent G1/S transition of TECs. In vitro studies using human TEC showed that (i) CRP activates Smad3 via both TGF-β-dependent and ERK/MAPK crosstalk mechanisms, (ii) Smad3 binds directly to p27, and (iii) blockade of Smad3 or the Fc receptor CD32 prevents CRP-induced p27-dependent G1 cell cycle arrest. In vivo, treatment of CRP Tg with a Smad3 inhibitor improved AKI outcomes. In their sum these data suggest that in CRP Tg mice undergoing AKI, impaired TEC regeneration is likely the result of CD32-Smad3-p27 driven inhibition of the CDK2/cyclin E complex. Targeting Smad3 may offer a new treatment approach for AKI.

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“…Skp2 promotes the polyubiquitination of p27 Kip1 and thus accelerates p27 Kip1 degradation 30 , thereby decreasing levels of p27 Kip1 . Normally p27 Kip1 binds to complexes of cyclins with their respective cyclin-dependent kinases (Cdk), thus preventing cyclin-Cdk complexes from phosphorylating their substrates 31 . Importantly, p27 Kip1 impairs the function of cyclin D-Cdk4/6 complexes 31 that are primarily responsible for promoting cell-cycle progression in G1 phase of the cell cycle 32, 33 .…”

Section: Introductionmentioning

confidence: 99%

Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D

et al. 2015

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The goal of this study was to determine whether and how adenosine affects the proliferation of human coronary artery smooth muscle cells (HCASMCs). In HCASMCs, 2-chloroadenosine (stable adenosine analogue), but not N6-cyclopentyladenosine, CGS21680, or N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide, inhibited HCASMC proliferation (A2B-receptor profile). 2-Chloroadenosine increased cAMP, reduced phosphorylation (activation) of ERK and Akt (protein kinases known to increase cyclin D expression and activity, respectively), and reduced levels of cyclin D1 (cyclin that promotes cell-cycle progression in G1). Moreover, 2-chloroadenosine inhibited expression of Skp2 (promotes proteolysis of p27Kip1) and up-regulated levels of p27Kip1 (cell-cycle regulator that impairs cyclin D function). 2-Chloroadenosine also inhibited signaling downstream of cyclin D including hyperphosphorylation of retinoblastoma protein and expression of cyclin A (S phase cyclin). Knockdown of A2B receptors prevented the effects of 2-chloroadenosine on ERK1/2, Akt, Skp2, p27Kip1, cyclin D1, cyclin A, and proliferation. Likewise, inhibition of adenylyl cyclase and protein kinase A abrogated 2-chloroadenosine’s inhibitory effects on Skp2 and stimulatory effects on p27Kip1, and rescued HCASMCs from 2-chloroadenosine-mediated inhibition. Knockdown of p27Kip1 also reversed the inhibitory effects of 2-chloroadenosine on HCASMC proliferation. In vivo, peri-arterial (rat carotid artery) 2-chloroadenosine (20 µmol/L for 7 days) down-regulated vascular expression of Skp2, up-regulated vascular expression of p27Kip1, and reduced neointima hyperplasia by 71% (p<0.05; neointimal thickness: control, 37,424±18,371 pixels; treated, 10,352±2,824 pixels). Conclusion The adenosine/A2B receptor/cAMP/protein kinase A axis inhibits HCASMC proliferation by blocking multiple signaling pathways (ERK1/2, Akt, and Skp2) that converge at cyclin D, a key G1 cyclin that controls cell-cycle progression.

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p27 and Leukemia: Cell Cycle and Beyond

Cited by 55 publications

References 130 publications

ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia

ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia

C-reactive protein promotes acute kidney injury via Smad3-dependent inhibition of CDK2/cyclin E

Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D

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