title: Cell cycle-specific function of Ikaros in human leukemia.
abstract: BACKGROUND
  The loss of Ikaros is associated with the development of B and T cell leukemia. Data on Ikaros function, including its role as a tumor suppressor and a regulator of cell cycle progression, come almost exclusively from murine studies; little is known of the mechanisms that regulate human Ikaros function. Our studies are the first to examine the function and regulation of human Ikaros isoforms during the cell cycle in human ALL.
  
  
  METHODS
  Electromobility shift assay (EMSA), confocal microscopy, and phosphopeptide mapping were used to study Ikaros function during different stages of the cell cycle.
  
  
  RESULTS
  The DNA-binding activity of human Ikaros complexes undergoes dynamic changes as the cell cycle progresses. In S phase, Ikaros DNA-binding affinity for regulatory regions of its target genes decreases, while its binding to pericentromeric heterochromatin is preserved and correlates with Ikaros pericentromeric localization. These S phase-specific changes in Ikaros function are controlled by phosphorylation via the CK2 kinase pathway. During cell cycle progression, the subcellular pericentromeric localization of the largest human Ikaros isoforms is different from that in mouse cells, suggesting unique functions for human Ikaros.
  
  
  CONCLUSIONS
  Our results demonstrate that the function of Ikaros is cell cycle-specific and controlled by CK2-mediated phosphorylation during S phase of the cell cycle in human T-cell and B-cell ALL. The differences we observe in murine and human Ikaros function highlight the importance of using human cells in studies of ALL. These data identify the CK2 pathway as a target for therapies in ALL.
authors: Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors: Zhanjun
authors: Z
authors: Li
authors: Chunhua
authors: C
authors: Song
authors: Hongsheng
authors: H
authors: Ouyang
authors: Liangxue
authors: L
authors: Lai
authors: Kimberly J
authors: KJ
authors: Payne
authors: Sinisa
authors: S
authors: Dovat
mesh_terms: D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D016196:S Phase
chemical_list: C497239:IKZF1 protein, human; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D051740:Ikaros Transcription Factor; D047390:Casein Kinase II