Less understood issues: p21Cip1 in mitosis and its therapeutic potential

Kreis, Nina-Naomi; Louwen, Frank; Yuan, Juping

doi:10.1038/onc.2014.133

Cited by 97 publications

(113 citation statements)

References 168 publications

(233 reference statements)

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“…A potential AD biomarker in lymphocytes seems to be the p21 protein, one of the most significant regulators of the G1/S checkpoint and the mediator of cell cycle arrest in the G1 phase [55]. In SAD lymphocytes an impaired progression of the G1/S phase occurs, consistent with p21's main change and its known function in arresting G1 [17].…”

Section: Dysregulated Cell Cycle In Lymphocytesmentioning

confidence: 72%

“…A few groups demonstrated a specific failure of the G1/S transition checkpoint in lymphocytes of AD patients (reviewed in [46]). This supports the AD cell cycle hypothesis of mitosis failure and validates using peripheral blood cells to study AD pathogenesis' molecular basis and search for AD biomarkers.A potential AD biomarker in lymphocytes seems to be the p21 protein, one of the most significant regulators of the G1/S checkpoint and the mediator of cell cycle arrest in the G1 phase [55]. In SAD lymphocytes an impaired progression of the G1/S phase occurs, consistent with p21's main change and its known function in arresting G1 [17].…”

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confidence: 72%

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Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Dysregulated Cell Cycle In Lymphocytesmentioning

confidence: 72%

mentioning

confidence: 72%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…The Cdk-interacting protein p21 Cip1/CDKN1A (p21) plays key roles in a broad range of cellular events like cell cycle regulation, apoptosis, differentiation, cytoskeletal dynamics, cell migration, gene transcription, DNA repair, reprogramming of induced pluripotent stem cells, aging and onset of senescence [1]. The transcription of p21 is regulated by p53-dependent [2] as well as -independent pathways [3].…”

Section: Introductionmentioning

confidence: 99%

Loss of p21Cip1/CDKN1A renders cancer cells susceptible to Polo-like kinase 1 inhibition

et al. 2014

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The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molecular anticancer therapy. While the preclinical results are encouraging, the clinical outcomes are rather less inspiring by showing limited anticancer activity. It is thus of importance to identify molecules and mechanisms responsible for the sensitivity of Polo-like kinase 1 inhibition. We have recently shown that p21Cip1/CDKN1A is involved in the regulation of mitosis and its loss prolongs the mitotic duration accompanied by defects in chromosome segregation and cytokinesis in various tumor cells. In the present study, we demonstrate that p21 affects the efficacy of Polo-like kinase 1 inhibitors, especially Poloxin, a specific inhibitor of the unique Polo-box domain. Intriguingly, upon treatment with Polo-like kinase 1 inhibitors, p21 is increased in the cytoplasm, associated with anti-apoptosis, DNA repair and cell survival. By contrast, deficiency of p21 renders tumor cells more susceptible to Polo-like kinase 1 inhibition by showing a pronounced mitotic arrest, DNA damage and apoptosis. Furthermore, long-term treatment with Plk1 inhibitors induced fiercely the senescent state of tumor cells with functional p21. We suggest that the p21 status may be a useful biomarker for predicting the efficacy of Plk1 inhibition.

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“…Another vital negative regulator is tumor suppressor p53, which is an essential downstream target of AMPK. Increased expression of p53 induces cell cycle arrest and/or apoptosis by modulating CDKs and CDKIs [47,48]. Previous studies have shown that AMPK activation upregulates the expression of p53 and p21 and down-regulates the expression cyclin E/CDK2, thus preventing cell cycle progression into S phase [49].…”

Section: Discussionmentioning

confidence: 99%

Zedoarondiol Inhibits Platelet-Derived Growth Factor-Induced Vascular Smooth Muscle Cells Proliferation via Regulating AMP-Activated Protein Kinase Signaling Pathway

Mao¹,

Tao²,

Song³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Vascular smooth muscle cells (VSMCs) proliferation contributes significantly to atherosclerosis and in-stent restenosis. Platelet-derived growth factor-BB (PDGF-BB) plays a vital role in VSMCs proliferation. Zedoarondiol, a sesquiterpene lactone compound, has an anti-inflammatory activity. However, the role of zedoarondiol in PDGF-BB-mediated VSMCs proliferation remains unclear. In this study, we investigated the effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation and explored the possible mechanisms. Methods: The inhibitory effects of zedoarondiol on PDGF-BB-induced VSMCs proliferation were evaluated by direct cell counting and the Cell Counting Kit-8 (CCK-8) assay. DNA synthesis was examined by bromodeoxyuridine (BrdU) incorporation assay. Cell cycle was assessed by propidium iodide staining. Western blotting was performed to determine the expression of cyclin-dependent kinase 2 (CDK2), cyclin E, p53, p21, total and phosphorylated adenosine monophosphate-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), mammalian target of rapamycin (mTOR), and p70 ribosomal protein S6 kinase (p70S6K). Results: Zedoarondiol suppressed PDGF-BB-induced VSMCs proliferation and DNA synthesis, and induced cell cycle arrest in G0/G1 phase. In addition, zedoarondiol activated AMPK and ACC, inhibited the phosphorylation of mTOR and p70S6K, increased the expression of p53 and p21, and decreased the expression of CDK2 and cyclin E. Compound C (an AMPK inhibitor) abrogated, whereas 5-aminoimidazole-4-carboxamide 1-β-ribofuranoside (AICAR, an AMPK activator) enhanced zedoarondiol-mediated inhibition of VSMCs proliferation and DNA synthesis. Conclusion: Zedoarondiol inhibits PDGF-BB-induced VSMCs proliferation via AMPK-mediated down-regulation of the mTOR/p70S6K pathway and up-regulation of the p53/p21 pathway. These findings suggest that zedoarondiol might be a promising compound against atherosclerosis and in-stent restenosis.

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Less understood issues: p21Cip1 in mitosis and its therapeutic potential

Cited by 97 publications

References 168 publications

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Loss of p21Cip1/CDKN1A renders cancer cells susceptible to Polo-like kinase 1 inhibition

Zedoarondiol Inhibits Platelet-Derived Growth Factor-Induced Vascular Smooth Muscle Cells Proliferation via Regulating AMP-Activated Protein Kinase Signaling Pathway

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