... 1.1 Service Provisioning Platform Design}}, author = {Pedrinaci, Carlos and Maleshkova, Maria... more ... 1.1 Service Provisioning Platform Design}}, author = {Pedrinaci, Carlos and Maleshkova, Maria and {\'A}lvaro Rey, Guillermo and Ruiz Moreno, Carlos and Dietze, Stefan and Gugliotta, Alessio and Merle, Philippe and Martinez, Ivan and Villa, Matteo and Abel, Sven}, language ...
Binding of different regulatory subunits and methylation of the catalytic (C) subunit carboxy-ter... more Binding of different regulatory subunits and methylation of the catalytic (C) subunit carboxy-terminal leucine 309 are two important mechanisms by which protein phosphatase 2A (PP2A) can be regulated. In this study, both genetic and biochemical approaches were used to investigate regulation of regulatory subunit binding by C subunit methylation. Monoclonal antibodies selectively recognizing unmethylated C subunit were used to quantitate the methylation status of wild-type and mutant C subunits. Analysis of 13 C subunit mutants showed that both carboxy-terminal and active site residues are important for maintaining methylation in vivo. Severe impairment of methylation invariably led to a dramatic decrease in Balpha subunit binding but not of striatin, SG2NA, or polyomavirus middle tumor antigen (MT) binding. In fact, most unmethylated C subunit mutants showed enhanced binding to striatin and SG2NA. Certain carboxy-terminal mutations decreased Balpha subunit binding without greatly af...
Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have... more Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2-ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2-ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) <5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value <0.05, log-rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. In the 139 patients from this study and from a 455-patie...
Gene expression profiles of malignant tumors surgically removed from ovarian cancer patients pre-... more Gene expression profiles of malignant tumors surgically removed from ovarian cancer patients pre-treated with chemotherapy (neo-adjuvant) prior to surgery group into two distinct clusters. One group clusters with carcinomas from patients not pre-treated with chemotherapy prior to surgery (C-L), while the other clusters with non-malignant adenomas (A-L). We show here that although the C-L cluster is preferentially associated with p53 loss-of-function (LOF) mutations, the C-L cluster cancer patients display a more favorable clinical response to chemotherapy as evidenced by enhanced long-term survivorships. Our results support a model whereby p53 mediated cell-cycle-arrest/DNA repair serves as a barrier to optimal chemotherapeutic treatment of ovarian and perhaps other carcinomas and suggest that inhibition of p53 during chemotherapy may enhance clinical outcome.
Clear cell papillary renal cell carcinoma is a distinct variant of renal cell carcinoma that shar... more Clear cell papillary renal cell carcinoma is a distinct variant of renal cell carcinoma that shares some overlapping histological and immunohistochemical features of clear cell renal cell carcinoma and papillary renal cell carcinoma. Although the clear cell papillary renal cell carcinoma immunohistochemical profile is well described, clear cell papillary renal cell carcinoma mRNA expression has not been well characterized. We investigated the clear cell papillary renal cell carcinoma gene expression profile using previously identified candidate genes. We selected 17 clear cell papillary renal cell carcinoma, 15 clear cell renal cell carcinoma, and 13 papillary renal cell carcinoma cases for molecular analysis following histological review. cDNA from formalin-fixed paraffin-embedded tissue was prepared. Quantitative real-time PCR targeting alpha-methylacyl coenzyme-A racemase (AMACR), BMP and activin membrane-bound inhibitor homolog (BAMBI), carbonic anhydrase IX (CA9), ceruloplasmin (CP), nicotinamide N-methyltransferase (NNMT), schwannomin-interacting protein 1 (SCHIP1), solute carrier family 34 (sodium phosphate) member 2 (SLC34A2), and vimentin (VIM) was performed. Gene expression data were normalized relative to 28S ribosomal RNA. Clear cell papillary renal cell carcinoma expressed all eight genes at variable levels. Compared with papillary renal cell carcinoma, clear cell papillary renal cell carcinoma expressed more CA9, CP, NNMT, and VIM, less AMACR, BAMBI, and SLC34A2, and similar levels of SCHIP1. Compared with clear cell renal cell carcinoma, clear cell papillary renal cell carcinoma expressed slightly less NNMT, but similar levels of the other seven genes. Although clear cell papillary renal cell carcinoma exhibits a unique molecular signature, it expresses several genes at comparable levels to clear cell renal cell carcinoma relative to papillary renal cell carcinoma. Understanding the molecular pathogenesis of clear cell papillary renal cell carcinoma will have a key role in future sub-classifications of this unique tumor.
... 1.1 Service Provisioning Platform Design}}, author = {Pedrinaci, Carlos and Maleshkova, Maria... more ... 1.1 Service Provisioning Platform Design}}, author = {Pedrinaci, Carlos and Maleshkova, Maria and {\&amp;amp;amp;amp;amp;amp;#x27;A}lvaro Rey, Guillermo and Ruiz Moreno, Carlos and Dietze, Stefan and Gugliotta, Alessio and Merle, Philippe and Martinez, Ivan and Villa, Matteo and Abel, Sven}, language ...
Binding of different regulatory subunits and methylation of the catalytic (C) subunit carboxy-ter... more Binding of different regulatory subunits and methylation of the catalytic (C) subunit carboxy-terminal leucine 309 are two important mechanisms by which protein phosphatase 2A (PP2A) can be regulated. In this study, both genetic and biochemical approaches were used to investigate regulation of regulatory subunit binding by C subunit methylation. Monoclonal antibodies selectively recognizing unmethylated C subunit were used to quantitate the methylation status of wild-type and mutant C subunits. Analysis of 13 C subunit mutants showed that both carboxy-terminal and active site residues are important for maintaining methylation in vivo. Severe impairment of methylation invariably led to a dramatic decrease in Balpha subunit binding but not of striatin, SG2NA, or polyomavirus middle tumor antigen (MT) binding. In fact, most unmethylated C subunit mutants showed enhanced binding to striatin and SG2NA. Certain carboxy-terminal mutations decreased Balpha subunit binding without greatly af...
Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have... more Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2-ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2-ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) <5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value <0.05, log-rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. In the 139 patients from this study and from a 455-patie...
Gene expression profiles of malignant tumors surgically removed from ovarian cancer patients pre-... more Gene expression profiles of malignant tumors surgically removed from ovarian cancer patients pre-treated with chemotherapy (neo-adjuvant) prior to surgery group into two distinct clusters. One group clusters with carcinomas from patients not pre-treated with chemotherapy prior to surgery (C-L), while the other clusters with non-malignant adenomas (A-L). We show here that although the C-L cluster is preferentially associated with p53 loss-of-function (LOF) mutations, the C-L cluster cancer patients display a more favorable clinical response to chemotherapy as evidenced by enhanced long-term survivorships. Our results support a model whereby p53 mediated cell-cycle-arrest/DNA repair serves as a barrier to optimal chemotherapeutic treatment of ovarian and perhaps other carcinomas and suggest that inhibition of p53 during chemotherapy may enhance clinical outcome.
Clear cell papillary renal cell carcinoma is a distinct variant of renal cell carcinoma that shar... more Clear cell papillary renal cell carcinoma is a distinct variant of renal cell carcinoma that shares some overlapping histological and immunohistochemical features of clear cell renal cell carcinoma and papillary renal cell carcinoma. Although the clear cell papillary renal cell carcinoma immunohistochemical profile is well described, clear cell papillary renal cell carcinoma mRNA expression has not been well characterized. We investigated the clear cell papillary renal cell carcinoma gene expression profile using previously identified candidate genes. We selected 17 clear cell papillary renal cell carcinoma, 15 clear cell renal cell carcinoma, and 13 papillary renal cell carcinoma cases for molecular analysis following histological review. cDNA from formalin-fixed paraffin-embedded tissue was prepared. Quantitative real-time PCR targeting alpha-methylacyl coenzyme-A racemase (AMACR), BMP and activin membrane-bound inhibitor homolog (BAMBI), carbonic anhydrase IX (CA9), ceruloplasmin (CP), nicotinamide N-methyltransferase (NNMT), schwannomin-interacting protein 1 (SCHIP1), solute carrier family 34 (sodium phosphate) member 2 (SLC34A2), and vimentin (VIM) was performed. Gene expression data were normalized relative to 28S ribosomal RNA. Clear cell papillary renal cell carcinoma expressed all eight genes at variable levels. Compared with papillary renal cell carcinoma, clear cell papillary renal cell carcinoma expressed more CA9, CP, NNMT, and VIM, less AMACR, BAMBI, and SLC34A2, and similar levels of SCHIP1. Compared with clear cell renal cell carcinoma, clear cell papillary renal cell carcinoma expressed slightly less NNMT, but similar levels of the other seven genes. Although clear cell papillary renal cell carcinoma exhibits a unique molecular signature, it expresses several genes at comparable levels to clear cell renal cell carcinoma relative to papillary renal cell carcinoma. Understanding the molecular pathogenesis of clear cell papillary renal cell carcinoma will have a key role in future sub-classifications of this unique tumor.
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Papers by Carlos Moreno