title: Separase loss of function cooperates with the loss of p53 in the initiation and progression of T- and B-cell lymphoma, leukemia and aneuploidy in mice.
abstract: BACKGROUND
  Cohesin protease Separase plays a key role in faithful segregation of sister chromatids by cleaving the cohesin complex at the metaphase to anaphase transition. Homozygous deletion of ESPL1 gene that encodes Separase protein results in embryonic lethality in mice and Separase overexpression lead to aneuploidy and tumorigenesis. However, the effect of Separase haploinsufficiency has not been thoroughly investigated.
  
  
  RESULTS
  Here we examined the effect of ESPL1 heterozygosity using a hypomorphic mouse model that has reduced germline Separase activity. We report that while ESPL1 mutant (ESPL1 (+/hyp)) mice have a normal phenotype, in the absence of p53, these mice develop spontaneous T- and B-cell lymphomas, and leukemia with a significantly shortened latency as compared to p53 null mice. The ESPL1 hypomorphic, p53 heterozygous transgenic mice (ESPL1(+/hyp), p53(+/-)) also show a significantly reduced life span with an altered tumor spectrum of carcinomas and sarcomas compared to p53(+/-) mice alone. Furthermore, ESPL1(+/hyp), p53(-/-) mice display significantly higher levels of genetic instability and aneuploidy in normal cells, as indicated by the abnormal metaphase counts and SKY analysis of primary splenocytes.
  
  
  CONCLUSIONS
  Our results indicate that reduced levels of Separase act synergistically with loss of p53 in the initiation and progression of B- and T- cell lymphomas, which is aided by increased chromosomal missegregation and accumulation of genomic instability. ESPL1(+/hyp), p53(-/-) mice provide a new animal model for mechanistic study of aggressive lymphoma and also for preclinical evaluation of new agents for its therapy.
authors.affiliation: Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Malini
authors.initials: M
authors.lastname: Mukherjee
authors.forename: Gouqing
authors.initials: G
authors.lastname: Ge
authors.forename: Nenggang
authors.initials: N
authors.lastname: Zhang
authors.forename: Eryong
authors.initials: E
authors.lastname: Huang
authors.forename: Lanelle V
authors.initials: LV
authors.lastname: Nakamura
authors.forename: Marissa
authors.initials: M
authors.lastname: Minor
authors.forename: Viacheslav
authors.initials: V
authors.lastname: Fofanov
authors.forename: Pullivarthi H
authors.initials: PH
authors.lastname: Rao
authors.forename: Alan
authors.initials: A
authors.lastname: Herron
authors.forename: Debananda
authors.initials: D
authors.lastname: Pati
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D004249:DNA Damage / Q000235:genetics; D018450:Disease Progression; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008136:Longevity / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D010641:Phenotype; D064247:Separase; D013953:Thymus Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D010450:Endopeptidases; C577987:ESPL1 protein, human; D064247:Separase