Phosphorylation of p62 by cdk1 Controls the Timely Transit of Cells through Mitosis and Tumor Cell Proliferation

Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Vontz Center for Molecular Studies, 3125 Eden Avenue, Cincinnati, OH 45267, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2010; 31(1):105-17. DOI: 10.1128/MCB.00620-10
Source: PubMed


The protein scaffold and signaling regulator p62 is important in critical cellular functions, including bone homeostasis, obesity, and cancer, because of its interactions with various signaling intermediaries. p62 is overexpressed in human cancers and is induced during cell transformation. Its genetic ablation inhibits lung tumorigenesis in vivo and cell proliferation in culture by regulating the TRAF6/NF-κB signaling cascade to control reactive oxygen species (ROS) production and apoptosis. Here we show that cdk1 phosphorylates p62 in vitro and in vivo at T269 and S272, which is necessary for the maintenance of appropriate cyclin B1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. The lack of cdk1-mediated phosphorylation of p62 leads to a faster exit from mitosis, which translates into enhanced cell proliferation and tumorigenesis in response to Ras-induced transformation. Therefore, p62 emerges as a node for the control of not only cell survival but also cell transit through mitosis.

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Available from: Maria Diaz Meco, Apr 09, 2014
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    • "In one of these studies, p62 is required for RAS to activate IKK through polyubiquitination of TRAF6 in lung adenocarcinomas . In normal and RAS-transformed cells, p62 controls timely transit of cells through mitosis and tumor cell proliferation (Linares et al., 2011). These previous findings are consistent with our observation that p62 is important for increased cell proliferation and G2/M transition in miR-146a low -expressing leukemic cells. "
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    ABSTRACT: Chromosome 5q deletions (del[5q]) are common in high-risk (HR) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR MDS/AML and miR-146a(-/-) hematopoietic stem/progenitor cells (HSPCs) results in TRAF6/NF-κB activation. Increased survival and proliferation of HSPCs from miR-146a(low) HR MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-κB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-κB signaling, as disrupting the p62-TRAF6 signaling complex results in cell-cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-κB to sustain TRAF6/NF-κB signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML.
    Cell Reports 09/2014; 8(5). DOI:10.1016/j.celrep.2014.07.062 · 8.36 Impact Factor
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    • "It has also been implicated in mitotic regulation (Moscat and Diaz-Meco, 2012). A recent report demonstrated that Cdk1 phosphorylates p62 to regulate Cyclin B levels during mitosis suggesting that p62 may play a role in SAC maintenance (Linares et al., 2011). Importantly, the authors demonstrate that expression of a non-phosphorylatable p62 increases lagging chromosome rates during anaphase and induces micronuclei formation, features which are consistent with the induction of CIN. "
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    ABSTRACT: Most solid tumors are characterized by abnormal chromosome numbers (aneuploidy) and karyotypic profiling has shown that the majority of these tumors are heterogeneous and chromosomally unstable. Chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis. Large-scale genome sequencing has failed to reveal frequent mutations of genes encoding proteins involved in mitosis. On the contrary, sequencing has revealed that most mutated genes in cancer fall into a limited number of core oncogenic signaling pathways that regulate the cell cycle, cell growth, and apoptosis. This led to the notion that the induction of oncogenic signaling is a separate event from the loss of mitotic fidelity, but a growing body of evidence suggests that oncogenic signaling can deregulate cell cycle progression, growth, and differentiation as well as cause CIN. These new results indicate that the induction of CIN can no longer be considered separately from the cancer-associated driver mutations. Here we review the primary causes of CIN in mitosis and discuss how the oncogenic activation of key signal transduction pathways contributes to the induction of CIN.
    Frontiers in Oncology 06/2013; 3:164. DOI:10.3389/fonc.2013.00164
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    • "CDK1 controls the checkpoint between the S/G2 and early mitotic phases. Importantly, p62 is phosphorylated by CDK1 on threonine 269 and serine 272 during the early mitotic phase, allowing the cells to properly continue through mitosis [82]. Moreover , these authors describe cancer cells expressing a non-phosphorylatable mutant of p62 that exhibit a better tumoral phenotype in vitro and in vivo than cells expressing the wild-type form of p62. "
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    ABSTRACT: Although p62/SQSTM1 was initially identified as an essential mediator of NFκB signaling, several recent studies have also highlighted its important role at the crossroad between the mTOR or MAPK signaling pathways and selective autophagy. The p62 structure containing important interaction domains attests to the ability of this protein to regulate and modulate the activation of these signaling pathways during tumor formation and propagation. The second very important function of this protein is to act as a molecular adaptor between the autophagic machinery and its substrates. Consequently, p62 is degraded following an increase in autophagic flux for which this protein currently serves as an indicator. However, the measurement of p62 expression strictly as a marker of autophagic flux is still controversial and can be misinterpreted mainly because this protein is subject to complex regulation at both the transcriptional and post-translational levels. Finally, because p62 is an autophagic substrate, it acts as a molecular link between cancer and autophagy by conferring a high level of selectivity through the degradation of important signaling molecules.
    American Journal of Cancer Research 08/2012; 2(4):397-413. · 4.17 Impact Factor
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