Low frequency of alterations of the α (PPP2R1A) and β (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms

Abstract

The phosphatase 2A (PP2A) is one of the major cellular serine-threonine phosphatases. It was recently shown that the gene encoding for the b isoform of its subunit A, PPP2R1B, is altered in human lung and colorectal carcinomas, suggesting a role in human tumorigenesis. Here, we report the detection of mutations in breast, lung carcinomas and melanomas in the genes of both a (PPP2R1A) and b isoforms. Mutations aecting PPP2R1B were found in four breast carcinomas, while mutations in PPP2R1A were found in carcinomas of the breast and of the lung and in one melanoma. Most of the mutations aecting PPP2R1B were exons deletions, suggesting abnormal splicing. These splicing abnormalities were detected in tumor samples in the absence of the normal splicing product, and were not found in several normal controls. In one case, a homozygous deletion present in tumor DNA, and not in the matched normal control was demonstrated. Mutations aecting the PPP2R1A gene were nucleotide substitutions changing highly conserved amino acids and one frame-shift. Although the frequency of alterations is low, the inclusion of both isoforms of subunit A in the genes mutated in human cancer and the addition of breast cancer to the list of neoplasms in which PPP2R1B is altered, strengthen the potential role of PP2A in human tumorogenesis.

Reduced expression of the A? subunit of protein phosphatase 2A in human gliomas in the absence of mutations in the A? and A? subunit genes

“…33 Furthermore, cancer-associated mutations were found in the gene encoding the A␤ subunit. [21][22][23] As in the case of A␣, most of the mutant A␤ subunits were defective in subunit interaction. 34 Therefore, it appears that A subunit function is hampered in cancer cells either as a result of gene mutation or changes in gene expression.…”

“…22 Importantly, we have shown that in every case the mutation renders the A␣ subunit defective in binding B or C subunits, depending on whether the mutation is located in the N-terminal B subunit binding domain (repeats 1-10) or in the C-terminal C subunit binding region (repeats [11][12][13][14][15] (Fig. 1).…”

“…1,17 Additional evidence for such a role came from the recent discovery that the gene encoding the A␤ subunit of PP2A, located on chromosome 11q23 in a region showing a high frequency of loss of heterozygosity (LOH), was mutated in 15% of primary lung tumors, 6% of lung tumor-derived cell lines and 15% of primary colon tumors. 21 In addition, both the A␣ and A␤ subunit isoforms of PP2A were found to be genetically altered in a variety of primary human cancers, 22 and mutations were described in the A␤ subunit gene in 4 colon cancer cases. 23 Further support for a role of PP2A in tumor suppression comes from the finding that the BЈ subunit of PP2A binds to the tumor suppressor adenomatous polyposis coli protein (APC) and downregulates the abundance of ␤-catenin in the Wnt signaling pathway, resulting in growth inhibition.…”

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

“…109 Mutations in the gene encoding the A subunit of PP2A have been found in human breast, lung, colon and colorectal carcinomas, and melanomas. 109,110 These mutations display defective or decreased binding to C subunit or B subunit of PP2A and therefore impair the normal functions of PP2A. 109,111,112 In addition, expression of the PP2A subunit Bg gene was found to be suppressed in human melanoma.…”

Restricted Protein Phosphatase 2A Targeting by Merkel Cell Polyomavirus Small T Antigen

“…Phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase, c-Myc, and other cancer signaling pathways that impact cellular processes, including cell cycle progression and cellular tumorigenesis are regulated by specific PP2A isoforms (9). Aberrant expression and mutations in PP2A subunits have been implicated in human cancers (8,(10)(11)(12)(13)(14)(15)(16). …”