The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function.
Mutations of the PPP2R1B gene, which encodes the Abeta scaffolding subunit of serine/threonine protein phosphatase 2A (PP2A), have been identified in several types of cancer including lung and breast carcinoma. One of these mutations results in an alteration of glycine 90 to aspartic acid (G90D), which has been found in both tumor and genomic DNA, raising the possibility that it is associated with an increased risk for cancer. A novel microarray-based technology was used to screen for this single-nucleotide polymorphism in 387 cancer patients and 329 control individuals. These data were used for case-control and family-based comparisons in order to study the association of this polymorphism with susceptibility to lung carcinoma, breast carcinoma, and acute lymphoblastic leukemia. The frequency of the G90D polymorphism in breast cancer patients was significantly higher in cases (3%) than in controls (0.3%). The wild-type Abeta subunit interacted with the B56gamma (PPP2R5C), PR72 (PPP2R3A), and PR48 subunits of PP2A but did not interact with the B55alpha (PPP2R2A), B56alpha (PPP2R5A), or B56beta (PPP2R5B) regulatory subunits in an in vitro binding assay. The G90D alteration inhibited the interaction of Abeta with the B56gamma subunit but had no effect on binding to the PR72 subunit. These results provide evidence that the G90D alteration of the Abeta subunit of PP2A is associated with a low frequency of breast carcinoma and that the role of this alteration in transformation is likely to involve decreased interaction with the B56gamma regulatory subunit.
Esplin
Edward D
ED
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390-9041, USA. edward.esplin@alumni.southwestern.edu
Ramos
Purita
P
Martinez
Bobbie
B
Tomlinson
Gail E
GE
Mumby
Marc C
MC
Evans
Glen A
GA
D019943:Amino Acid Substitution; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D005260:Female; D005822:Genetic Vectors; D005998:Glycine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D054648:Protein Phosphatase 2
D017931:DNA Primers; D001224:Aspartic Acid; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D005998:Glycine