Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase

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• 作者：Kleiton S Borges (1) (2)
  Valerie A Arboleda (1) (3)
  Eric Vilain (1) (4) (5)
  
  1. Department of Human Genetics ; David Geffen School of Medicine at UCLA ; University of California ; Los Angeles ; 695 Charles E. Young Drive ; Los Angeles ; CA ; 90095 ; USA
  2. Department of Genetics ; Ribeir茫o Preto Medical School ; University of S茫o ; Ribeir茫o Preto ; Av. Bandeirantes 3900 ; CEP 14049-900 ; Ribeir茫o Preto ; SP ; Brazil
  3. Department of Pathology and Laboratory Medicine ; David Geffen School of Medicine at UCLA ; University of California ; Los Angeles ; USA
  4. Department of Pediatrics ; David Geffen School of Medicine ; University of California ; Los Angeles ; USA
  5. Department of Urology ; David Geffen School of Medicine ; University of California ; Los Angeles ; USA
  
• 关键词：Cell cycle ; CDK ; inhibitor ; IMAGe syndrome ; Cyclin ; Beckwith Wiedemann syndrome ; Intrauterine growth restriction
• 刊名：Cell Division
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：10
• 期：1
• 全文大小：1,050 KB
• 参考文献：1. Matsuoka, S, Edwards, MC, Bai, C, Parker, S, Zhang, P, Baldini, A (1995) p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. Genes Dev 9: pp. 650-62 CrossRef
  2. Matsuoka, S, Thompson, JS, Edwards, MC, Bartletta, JM, Grundy, P, Kalikin, LM (1996) Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15. Proc Natl Acad Sci U S A 93: pp. 3026-30 CrossRef
  3. Romanelli, V, Belinch贸n, A, Benito-Sanz, S, Mart铆nez-Glez, V, Gracia-Bouthelier, R, Heath, KE (2010) CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms. Am J Med Genet A 152A: pp. 1390-7
  4. Arboleda, VA, Lee, H, Parnaik, R, Fleming, A, Banerjee, A, Ferraz-de-Souza, B (2012) Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet 44: pp. 788-92 CrossRef
  5. Nishitani, H, Shiomi, Y, Iida, H, Michishita, M, Takami, T, Tsurimoto, T (2008) CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation. J Biol Chem 283: pp. 29045-52 CrossRef
  6. Brioude, F, Oliver-Petit, I, Blaise, A, Praz, F, Rossignol, S, Jule, ML (2013) CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet 50: pp. 823-30 CrossRef
  7. Hamajima, N, Johmura, Y, Suzuki, S, Nakanishi, M, Saitoh, S (2013) Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome. PLoS One 8: pp. e75137 CrossRef
  8. Girard, F, Strausfeld, U, Fernandez, A, Lamb, NJ (1991) Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67: pp. 1169-79 CrossRef
  9. Watanabe, H, Pan, ZQ, Schreiber-Agus, N, DePinho, RA, Hurwitz, J, Xiong, Y (1998) Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen. Proc Natl Acad Sci U S A 95: pp. 1392-7 CrossRef
  10. Chen, B, Zhao, R, Su, CH, Linan, M, Tseng, C, Phan, L (2012) CDK inhibitor p57 (Kip2) is negatively regulated by COP9 signalosome subunit 6. Cell Cycle 11: pp. 4633-41 CrossRef
  11. Zhao, R, Yang, HY, Shin, J, Phan, L, Fang, L, Che, TF (2013) CDK inhibitor p57 (Kip2) is downregulated by Akt during HER2-mediated tumorigenicity. Cell Cycle 12: pp. 935-43 CrossRef
  12. Andrews, SC, Wood, MD, Tunster, SJ, Barton, SC, Surani, MA, John, RM (2007) Cdkn1c (p57Kip2) is the major regulator of embryonic growth within its imprinted domain on mouse distal chromosome 7. BMC Dev Biol 21: pp. 53 CrossRef
  13. Kato, F, Hamajima, T, Hasegawa, T, Amano, N, Horikawa, R, Nishimura, G (2014) IMAGe syndrome: clinical and genetic implications based on investigations in three Japanese patients. Clin Endocrinol 80: pp. 706-13 CrossRef
  14. Kerns, SL, Guevara-Aguirre, J, Andrew, S, Geng, J, Guevara, C, Guevara-Aguirre, M (2014) A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. J Clin Endocrinol Metab 99: pp. 2117-22 CrossRef
  
• 刊物主题：Cell Biology; Cancer Research;
• 出版者：BioMed Central
• ISSN：1747-1028

文摘

CDKN1C (also known as P57 kip2 ) is a cyclin-dependent kinase inhibitor that functions as a negative regulator of cell proliferation through G1 phase cell cycle arrest. Recently, our group described gain-of-function mutations in the PCNA-binding site of CDKN1C that result in an undergrowth syndrome called IMAGe Syndrome (Intrauterine Growth Restriction, Metaphyseal dysplasia, Adrenal hypoplasia, and Genital anomalies), with life-threatening consequences. Loss-of-function mutations in CDKN1C have been identified in 5-10% of individuals with Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder with features that are the opposite of IMAGe syndrome. Here, we investigate the effects of IMAGe-associated mutations on protein stability, cell cycle progression and cell proliferation. Mutations in the PCNA-binding site of CDKN1C significantly increase CDKN1C protein stability and prevent cell cycle progression into the S phase. Overexpression of either wild-type or BWS-mutant CDKN1C inhibited cell proliferation. However, the IMAGe-mutant CDKN1C protein decreased cell growth significantly more than both the wild-type or BWS protein. These findings bring new insights into the molecular events underlying IMAGe syndrome.