Lee MH, Reynisdottir I, Massague J.. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev 9: 639-649

Cell Biology and Genetics Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Genes & Development (Impact Factor: 10.8). 04/1995; 9(6):639-49. DOI: 10.1101/gad.9.6.639
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Progression through the cell cycle is catalyzed by cyclin-dependent kinases (CDKs) and is negatively controlled by CDK inhibitors (CDIs). We have isolated a new member of the p21CIP1/p27KIP1 CDI family and named it p57KIP2 to denote its apparent molecular mass and higher similarity to p27KIP1. Three distinct p57 cDNAs were cloned that differ at the start of their open reading frames and correspond to messages generated by the use of distinct splice acceptor sites. p57 is distinguished from p21 and p27 by its unique domain structure. Four distinct domains follow the heterogeneous amino-terminal region and include, in order, a p21/p27-related CDK inhibitory domain, a proline-rich (28% proline) domain, an acidic (36% glutamic or aspartic acid) domain, and a carboxy-terminal nuclear targeting domain that contains a putative CDK phosphorylation site and has sequence similarity to p27 but not to p21. Most of the acidic domain consists of a novel, tandemly repeated 4-amino acid motif. p57 is a potent inhibitor of G1- and S-phase CDKs (cyclin E-cdk2, cyclin D2-cdk4, and cyclin A-cdk2) and, to lesser extent, of the mitotic cyclin B-Cdc2. In mammalian cells, p57 localizes to the nucleus, associates with G1 CDK components, and its overexpression causes a complete cell cycle arrest in G1 phase. In contrast to the widespread expression of p21 and p27 in human tissues, p57 is expressed in a tissue-specific manner, as a 1.5-kb species in placenta and at lower levels in various other tissues and a 7-kb mRNA species observed in skeletal muscle and heart. The expression pattern and unique domain structure of p57 suggest that this CDI may play a specialized role in cell cycle control.

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    • "Also, p27 has the capacity to arrest cells in G2 (Niculescu et al., 1998). p57 (Kip2) inhibits cyclin A-and E-associated CDKs and therefore regulates G1/S transition and completion of S phase (Lee et al., 1995) and is primarily expressed in terminally differentiated cells (Yan et al., 1997). IUGR is a major cause of perinatal death and neonatal morbidity and mortality. "
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    ABSTRACT: Intrauterine growth restriction (IUGR) is a major clinical problem, which causes perinatal morbidity and mortality. One of the reasons for IUGR is abnormal placentation. In rats, fetal-placental exposure to maternally administered glucocorticoids decreases birth weight and placental weight. Proper placental development depends on the proliferation and differentiation of trophoblasts. Our knowledge about the mitotic regulators that play key roles in synchronizing these events is limited. Also the mechanisms underlying the placental growth inhibitory effects of glucocorticoids have not been elucidated. The aim of this study was to investigate the immunolocalization, mRNA and protein levels of proliferating cell nuclear antigen (PCNA), cyclin D3, p27 and p57 in normal and dexamethasone-induced IUGR Wistar rat placentas by reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry and Western blot. We also compared apoptotic cell numbers at the light microscopic level via terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) and transmission electron microscopy. Glucocorticoid levels were higher in IUGR rats than in control rats after 60 and 120min of injection. We showed reduced gene and protein expressions of PCNA and cyclin D3 and increased expressions of p27 and p57 in IUGR placentas compared to control placentas. Apoptotic cell number was higher in the placentas of the IUGR group. In brief we found that maternal dexamethasone treatment led to a shift from cell proliferation to apoptosis in IUGR placentas. Dexamethasone induced placental and embryonal abnormalities which could be associated with reduced expressions of PCNA and cyclin D3, increased expressions of p27 and p57 and increased rate of apoptosis in IUGR placentas. Copyright © 2014 Elsevier GmbH. All rights reserved.
    Acta Histochemica 01/2015; 117(2). DOI:10.1016/j.acthis.2014.11.010 · 1.71 Impact Factor
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    • "The p57Kip2 protein (abbreviated as p57) is a member of p21Cip1/p27Kip1 CDI family, sharing similar sequence with p27Kip1, also known as CDKN1C. Its overexpression causes a complete cell cycle arrest in G1 phase [42]. Decreased expression of p57 has been found in many types of cancer, including bladder carcinoma, gastric cancer and pancreatic cancer [43]. "
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    ABSTRACT: CSN6 is one subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), which is an evolutionarily conserved multiprotein complex found in plants and animals and originally described as a repressor of light-dependent growth and transcription in Arabidopsis. CSN is homologous to the 19S lid subcomplex of the 26S proteasome, thus it has been postulated to be a regulator of the ubiquitin-proteasome pathway. In mammalian cells, it consists of eight subunits (CSN1-CSN8). Among the CSN subunits, CSN5 and CSN6 are the only two that each contains an MPN (Mpr1p and Pad1p N-terminal) domain. The deneddylating activity of an MPN domain toward cullin-RING ubiquitin ligases (CRL) may coordinate CRL-mediated ubiquitination activity. More and more studies about CSN6 are emerging, and its overexpression is found in many types of cancers. Evidence has shown that CSN6 is a molecule platform between protein degradation and signal transduction. Here, we provide a summary of human CSN6, especially its roles in cancer, hoping that it can lay the groundwork for cancer prevention or therapy.
    Cell Division 11/2013; 8(1):14. DOI:10.1186/1747-1028-8-14 · 3.53 Impact Factor
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    • "CDKN1C (p57Kip2), CDKN1A (p21Cip1), and CDKN1B (p27Kip1) belong to the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors (Figure 1A), which negatively regulate cell cycle progression by inhibiting G1 CDKs [10], [11]. The CDKN1C gene is located at 11p11.5, which harbors a cluster of imprinted genes and is expressed only from the maternal allele. "
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    ABSTRACT: Mutations in the proliferating cell nuclear antigen (PCNA)-binding domain of the CDKN1C gene were recently identified in patients with IMAGe syndrome. However, loss of PCNA binding and suppression of CDKN1C monoubiquitination by IMAGe-associated mutations hardly explain the reduced-growth phenotype characteristic of IMAGe syndrome. We demonstrate here that IMAGe-associated mutations in the CDKN1C gene dramatically increased the protein stability. We identified a novel heterozygous mutation, c.815T>G (p.Ile272Ser), in the CDKN1C gene in three siblings manifesting clinical symptoms associated with IMAGe syndrome and their mother (unaffected carrier). PCNA binding to CDKN1C was disrupted in the case of p.Ile272Ser, and for two other IMAGe-associated mutations, p.Asp274Asn and p.Phe276Val. Intriguingly, the IMAGe-associated mutant CDKN1C proteins were fairly stable even in the presence of cycloheximide, whereas the wild-type protein was almost completely degraded via the proteasome pathway, as shown by the lack of degradation with addition of a proteasome inhibitor, MG132. These results thus suggested that the reduced-growth phenotype of IMAGe syndrome derives from CDKN1C gain-of-function due to IMAGe-associated mutations driving increased protein stability.
    PLoS ONE 09/2013; 8(9):e75137. DOI:10.1371/journal.pone.0075137 · 3.23 Impact Factor
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