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.

METHODOLOGY/PRINCIPAL FINDINGS:

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/SIGNIFICANCE:

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: Malini Mukherjee, Gouqing Ge, Nenggang Zhang, Eryong Huang, Lanelle V Nakamura, Marissa Minor, Viacheslav Fofanov, Pullivarthi H Rao, Alan Herron, Debananda Pati
• Journal: PloS one (PLoS One) Vol. 6 Issue 7 Pg. e22167 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21799785 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cell Cycle Proteins
• Tumor Suppressor Protein p53
• Endopeptidases
• ESPL1 protein, human
• Separase

Topics

• Aneuploidy
• Animals
• Bone Marrow (metabolism, pathology)
• Cell Cycle Proteins (deficiency, genetics, metabolism)
• Cell Proliferation
• DNA Damage (genetics)
• Disease Progression
• Endopeptidases (deficiency, genetics, metabolism)
• Female
• Humans
• Leukemia (enzymology, genetics, pathology)
• Longevity (genetics)
• Lymphoma, B-Cell (enzymology, genetics, pathology)
• Lymphoma, T-Cell (enzymology, genetics, pathology)
• Mice
• Neoplasm Metastasis
• Phenotype
• Separase
• Thymus Neoplasms (enzymology, genetics, pathology)
• Tumor Suppressor Protein p53 (deficiency, genetics, metabolism)