title: Expression of p27(Kip1) and c-Jun activation binding protein 1 are inversely correlated in systemic anaplastic large cell lymphoma.
abstract: OBJECTIVE
  p27(Kip1)(p27) is a universal cyclin-dependent kinase inhibitor that inhibits cell cycle transition from G(1) to S phase and is primarily regulated at the post-transcriptional level via the ubiquitin-proteasome pathway. In vitro data suggest that p27 degradation may be accelerated by the c-Jun activation domain binding protein-1 (JAB1), originally identified as a coactivator of the gene regulatory AP-1 proteins. We assessed p27 and JAB1 in systemic anaplastic large cell lymphoma (ALCL), a group of tumors in which a substantial subset overexpresses anaplastic lymphoma kinase (ALK).
  
  
  METHODS
  The study included 5 ALK-positive ALCL cell lines, namely Karpas 299, JB-6, SR-786, SU-DHL1, and TG-S1, and 66 ALCL tumors (24 ALK positive and 42 ALK negative). The cell lines were analyzed by Western blot methods, and the tumors were assessed immunohistochemically.
  
  
  RESULTS
  SU-DHL1 and TG-S1 cells were positive for p27 and negative for JAB1, whereas SR-786 and JB-6 cells were positive for JAB-1 but negative for p27. Karpas 299 expressed p27 at relatively low levels and JAB1 at high levels. Using a 10% cutoff, p27 was positive in 12 of 66 (18.2%) ALCL tumors (5 ALK positive and 7 ALK negative), whereas JAB1 was detected in 47 of 53 (88.7%) tumors (15 ALK positive and 32 ALK negative) assessed. p27 and JAB1 expression were inversely correlated (Spearman r = -0.27, P = 0.03). For 54 ALCL patients with complete follow-up, and in separate analyses of patients with ALK-positive or -negative tumors, p27 expression correlated with poorer prognosis.
  
  
  CONCLUSIONS
  p27 is absent or expressed at low levels in most ALCL tumors and inversely correlates with JAB1. These findings suggest that JAB1-mediated degradation of p27, allowing cell cycle progression, may play a role in the pathogenesis of ALCL.
authors.affiliation: Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Claret
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Qingxiu
authors.initials: Q
authors.lastname: Zhang
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Sarris
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonnell
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D015153:Blotting, Western; D000075686:COP9 Signalosome Complex; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D008875:Middle Aged; D010447:Peptide Hydrolases; D010766:Phosphorylation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex