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PMID:23657012

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Citation

Bowman-Colin, C, Xia, B, Bunting, S, Klijn, C, Drost, R, Bouwman, P, Fineman, L, Chen, X, Culhane, AC, Cai, H, Rodig, SJ, Bronson, RT, Jonkers, J, Nussenzweig, A, Kanellopoulou, C and Livingston, DM (2013) Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer. Proc. Natl. Acad. Sci. U.S.A. 110:8632-7

Abstract

Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germ-line deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1-mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2- or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can now be explored genetically in vivo.

Links

PubMed PMC3666744 Online version:10.1073/pnas.1305362110

Keywords

Animals; BRCA1 Protein/genetics; BRCA1 Protein/metabolism; BRCA2 Protein/genetics; BRCA2 Protein/metabolism; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Disease Models, Animal; Female; Gene Deletion; Humans; Mammary Neoplasms, Experimental/genetics; Mammary Neoplasms, Experimental/metabolism; Mammary Neoplasms, Experimental/pathology; Mice; Mice, Mutant Strains; Neoplastic Syndromes, Hereditary/genetics; Neoplastic Syndromes, Hereditary/metabolism; Neoplastic Syndromes, Hereditary/pathology; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Rad51 Recombinase/genetics; Rad51 Recombinase/metabolism; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PALB2

acts_upstream_of_or_within

GO:0001701: in utero embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5495930

P

Seeded From UniProt

complete

MOUSE:PALB2

acts_upstream_of_or_within

GO:0048568: embryonic organ development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5495930

P

Seeded From UniProt

complete

MOUSE:PALB2

acts_upstream_of_or_within

GO:0035264: multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5495930

P

Seeded From UniProt

complete

Notes

See also

References

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