CDK Inhibitors : Cell Cycle regulators and Beyond

Université de Toulouse - LBCMCP and CNRS - UMR5088, Toulouse, France.
Developmental Cell (Impact Factor: 9.71). 03/2008; 14(2):159-69. DOI: 10.1016/j.devcel.2008.01.013
Source: PubMed


First identified as cell cycle inhibitors mediating the growth inhibitory cues of upstream signaling pathways, the cyclin-CDK inhibitors of the Cip/Kip family p21Cip1, p27Kip1, and p57Kip2 have emerged as multifaceted proteins with functions beyond cell cycle regulation. In addition to regulating the cell cycle, Cip/Kip proteins play important roles in apoptosis, transcriptional regulation, cell fate determination, cell migration and cytoskeletal dynamics. A complex phosphorylation network modulates Cip/Kip protein functions by altering their subcellular localization, protein-protein interactions, and stability. These functions are essential for the maintenance of normal cell and tissue homeostasis, in processes ranging from embryonic development to tumor suppression.

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Available from: James M Roberts, Dec 17, 2013
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    • "These results demonstrate the role of Lgl in suppression of cell proliferation in confluent culture conditions. At the molecular level, p27kip1 (p27), which binds to cyclin-CDK complexes and causes G1 cell cycle arrest, is upregulated in G0/G1-arrested cells such as contact inhibited or serum-starved cells (Polyak et al., 1994; Coats et al., 1996; Besson et al., 2008). In control cells, p27 but not other cell cycle inhibitors, p16 and p21, was upregulated as cell density increased. "
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    ABSTRACT: Lethal giant larvae (Lgl) is an evolutionarily conserved tumor suppressor, whose loss of function causes disrupted epithelial architecture with enhanced cell proliferation and defects in cell polarity. A role for Lgl in the establishment and maintenance of cell polarity, via suppression of the PAR-aPKC polarity complex, is established; however, the mechanism by which Lgl regulates cell proliferation remains not fully understood. Here we show that depletion of Lgl1 and Lgl2 in MDCK epithelial cells results in overproliferation, and overproduction of Lgl2 causes G1 arrest. We also show that Lgl associates with the VprBP-DDB1 complex independently of the PAR-aPKC complex and prevents the VprBP-DDB1 subunits from binding to Cul4A, a central component of the CRL4 [VprBP] ubiquitin E3 ligase complex implicated in G1 to S phase progression. Consistently, depletion of VprBP or Cul4 rescues the overproliferation of Lgl-depleted cells. In addition, the affinity between Lgl2 and the VprBP-DDB1 complex increases at high cell density. Further, aPKC-mediated phosphorylation of Lgl2 negatively regulates the interaction between Lgl2 and VprBP-DDB1 complex. These results suggest a mechanism protecting overproliferation of epithelial cells where Lgl play a critical role to inhibit formation of the CRL4 [VprBP] complex resulting in G1 arrest. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 05/2015; 26(13). DOI:10.1091/mbc.E14-10-1462 · 4.47 Impact Factor
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    • "These data suggest that CPR5 and SIM/SMR1 may signal through E2F during the plant immune response. SIAMESE/SIAMESE-RELATED 1 and E2F Are Required for Pathogen Effector-Triggered Programmed Cell Death and Immunity Our microarray data suggest that like mammalian Cip/Kip proteins , which are known to play a key role in integrating stress signals into cell fate determination (Besson et al., 2008), plant CKIs and E2Fs may be important regulators of PCD in response to pathogen challenge. This is consistent with the genetic data showing that the cpr5-associated PCD in cotyledons was fully suppressed by both sim smr1 and e2fabc (Figures 3A and 3B). "
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    ABSTRACT: Effector-triggered immunity (ETI), the major host defense mechanism in plants, is often associated with programmed cell death (PCD). Plants lack close homologs of caspases, the key mediators of PCD in animals. So although the NB-LRR receptors involved in ETI are well studied, how they activate PCD and confer disease resistance remains elusive. We show that the Arabidopsis nuclear envelope protein, CPR5, negatively regulates ETI and the associated PCD through a physical interaction with cyclin-dependent kinase inhibitors (CKIs). Upon ETI induction, CKIs are released from CPR5 to cause overactivation of another core cell-cycle regulator, E2F. In cki and e2f mutants, ETI responses induced by both TIR-NB-LRR and CC-NB-LRR classes of immune receptors are compromised. We further show that E2F is deregulated during ETI, probably through CKI-mediated hyperphosphorylation of retinoblastoma-related 1 (RBR1). This study demonstrates that canonical cell-cycle regulators also play important noncanonical roles in plant immunity. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cell Host & Microbe 11/2014; 16(6). DOI:10.1016/j.chom.2014.10.005 · 12.33 Impact Factor
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    • "Decreases in levels of POU5F1 and NANOG occurred later than the decrease in the levels of SOX2. It has been shown that P21 can modulate transcription by directly binding to specific promoters in a cell cycle-independent manner (Devgan et al., 2005; Besson et al., 2008). A recent study has shown that P21 directly binds to a Sox2 enhancer and negatively regulates Sox2 expression in neural stem cells (Marqués-Torrejon et al., 2013). "
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