p27 as Jekyll and Hyde: Regulation of cell cycle and cell motility

Larrea, Michelle D.; Wander, Seth A.; Slingerland, Joyce M.

doi:10.4161/cc.8.21.9789

Cited by 107 publications

(116 citation statements)

References 71 publications

(103 reference statements)

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“…10B). The slightly negative effect of the p27_6 siRNA on MCF-10A cell proliferation is consistent with the notion that p27 KIP1 facilitates the assembly and nuclear import of cyclin D1-Cdk4 complexes (31). Thus, in MCF-10A cells, simultaneous silencing of p21 WAF1/CIP1 and p27 KIP1 protein expression that mimics the regulatory effect of ATM inhibition on these cell cycle regulators results in a 2.4-fold net proliferative increase, similar to that observed after ATM inhibition (Fig.…”

Section: Kip1supporting

confidence: 71%

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

Mandriota

Buser

Lesne

et al. 2010

Journal of Biological Chemistry

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Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/ SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasomedependent reduction of p21 WAF1/CIP1 and p27 KIP1 protein levels, whereas little or no effect was observed on p21 WAF1/CIP1 or p27 KIP1 mRNAs. p21 WAF1/CIP1 silencing also increased MCF-10A cell proliferation, thus identifying p21 WAF1/CIP1 down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.

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Section: Kip1supporting

confidence: 71%

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

Mandriota

Buser

Lesne

et al. 2010

Journal of Biological Chemistry

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“…As shown in Figure 2e, PIM1 reduction correlates with the decrease of threonine157 phosphorylation. As phosphorylation on this site (together with threonine198) has been shown to inhibit p27 Kip1 activity and induce its degradation (Larrea et al, 2009), our results indicate that the decline of PIM1 level could cause stabilization and activation of p27 Kip1 .…”

Section: Effect Of Rps19 Deficiencymentioning

confidence: 57%

PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

et al. 2010

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PIM1 is a constitutively active serine/threonine kinase regulated by cytokines, growth factors and hormones. It has been implicated in the control of cell cycle progression and apoptosis and its overexpression has been associated with various kinds of lymphoid and hematopoietic malignancies. The activity of PIM1 is dependent on the phosphorylation of several targets involved in transcription, cell cycle and apoptosis. We have recently observed that PIM1 interacts with ribosomal protein (RP)S19 and cosediments with ribosomes. Defects in ribosome synthesis (ribosomal stress) have been shown to activate a p53-dependent growth arrest response. To investigate if PIM1 could have a role in the response to ribosomal stress, we induced ribosome synthesis alterations in TF-1 and K562 erythroid cell lines. We found that RP deficiency, induced by RNA interference or treatment with inhibitor of nucleolar functions, causes a drastic destabilization of PIM1. The lower level of PIM1 induces an increase in the cell cycle inhibitor p27 Kip1 and blocks cell proliferation even in the absence of p53. Notably, restoring PIM1 level by transfection causes a recovery of cell growth. Our data indicate that PIM1 may act as a sensor for ribosomal stress independently of or in concert with the known p53-dependent mechanisms.

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“…Accumulating data suggest that p27 has another role in regulating cell motility and migration independent of its cellcycle role. p27 increases the stability of actin stress fibers by binding to and inhibiting RhoA in cytoplasm, which results in an increase in cell motility (35). As HGF treatment increases the motility of HepG2 cells, leading to cell scattering, the upregulation of p27 might contribute to the increased cell motility with HGF.…”

Section: Discussionmentioning

confidence: 99%

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

Bian²,

Takizawa³

et al. 2013

Molecular Cancer Research

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Hepatocyte growth factor (HGF) has an inhibitory effect on human HepG2 hepatoma cell proliferation. Previously, it was shown that HGF treatment downregulated Id1 and upregulated p16 INK4a in an ERK-dependent manner, leading to the inhibition of cellular proliferation. Here, new insight suggests that Skp2, an SCF complex component and potential prognosticator in cancer, is downregulated by injection of HGF into established HepG2 xenograft tumors. The downregulation was evident at both the mRNA and protein level and in an ERK-dependent manner. Critically, high expression of Skp2 restored HGF-inhibited cell proliferation, indicating that the inhibitory effect of HGF required the downregulation of Skp2. However, downregulation was not involved in the HGFinduced upregulation of a CDK inhibitor, p27 Kip1 , a known SCF-Skp2 target. Instead, data revealed that Skp2 regulated Myc activity, which has oncogenic potential in the generation of hepatocellular carcinoma. Elevated expression of Skp2 or a mutant that is unable to associate with the SCF complex was capable of activating Myc, suggesting that Skp2 does not act on Myc as a component of the SCF complex, and thus functions as an activator of Myc independent of its role in ubiquitination. Furthermore, Skp2 regulated Id1 expression by regulating Myc activity, and the regulation of Skp2 is involved in the activity of p16 promoter through regulation of Id1 expression. Overall, these mechanistic findings provide the first evidence that ERK-dependent downregulation of Skp2 reduced Myc activity, leading to HGF-induced inhibition of cell proliferation through decreased Id1 expression.

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p27 as Jekyll and Hyde: Regulation of cell cycle and cell motility

Cited by 107 publications

References 71 publications

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

PIM1 kinase is destabilized by ribosomal stress causing inhibition of cell cycle progression

ERK-Dependent Downregulation of Skp2 Reduces Myc Activity with HGF, Leading to Inhibition of Cell Proliferation through a Decrease in Id1 Expression

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