Regulatory subunit type I‐α of protein kinase A (<i>PRKAR1A</i>): A tumor‐suppressor gene for sporadic thyroid cancer

Sandrini, Fabiano; Matyakhina, Ludmila; Sarlis, Nicholas J.; Kirschner, Lawrence S.; Farmakidis, Constantine; Gimm, Oliver; Stratakis, Constantine A.

doi:10.1002/gcc.10112

Cited by 83 publications

(72 citation statements)

References 59 publications

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“…Of the down-regulated genes, DUSP 1, which has known proliferation and differentiation functions, has been shown previously to be down-regulated in follicular carcinomas (17) and in advanced epithelial ovarian cancer (30). We also noted the PKIA gene, a potent inhibitor of protein kinase B, to be down-regulated in follicular carcinomas compared with adenomas, supporting previous molecular studies of sporadic thyroid cancer (31). As in earlier studies, the VEGF gene was characteristically noted in follicular carcinomas (32,33).…”

Section: Discussionsupporting

confidence: 88%

Gene Expression Profiling of Differentiated Thyroid Neoplasms

Chevillard¹,

Ugolin²,

Vielh

et al. 2004

Clinical Cancer Research

120

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Purpose: The purpose of this research was to identify novel genes that can be targeted as diagnostic and clinical markers of differentiated thyroid tumors.Experimental Design: Gene expression analysis using microarray platform was performed on 6 pathologically normal thyroid samples and 12 primary follicular and papillary thyroid neoplasms. Microarrays containing probes for 5,760 human full-length cDNAs were used for hybridization with total RNA from normal and tumor thyroid samples labeled with Cy3-dUTP and Cy5-dUTP, respectively. Scanned array images were recorded, and data analysis was performed. Selected sets of differentially expressed genes were analyzed using quantitative real-time reverse transcription-PCR for verification.Results: We identified 155 genes that differentiate histologically normal thyroid tissues from benign and malignant thyroid neoplasms. Of these 75 genes were differentiated between follicular neoplasms (adenoma and carcinoma) and the follicular variant of papillary carcinoma. Purely follicular neoplasms (adenomas and carcinomas) shared many genetic profiles, and only 43 genes were distinctly different between these tumors. Hierarchical cluster analysis also differentiated conventional papillary carcinoma from its follicular variant and follicular tumors. The differentially expressed genes were composed of members of cell differentiation, adhesion, immune response, and proliferation associated pathways. Quantitative real-time reverse transcription-PCR analysis of selected genes corroborated the microarray expression results.Conclusions: Our study show the following: (1) differences in gene expression between tumor and nontumor bearing normal thyroid tissue can be identified, (2) a set of genes differentiate follicular neoplasm from follicular variant of papillary carcinoma, (3) follicular adenoma and carcinoma share many of the differentiated genes, and (4) gene expression differences identify conventional papillary carcinoma from the follicular variant.

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Section: Discussionsupporting

confidence: 88%

Gene Expression Profiling of Differentiated Thyroid Neoplasms

Chevillard¹,

Ugolin²,

Vielh

et al. 2004

Clinical Cancer Research

120

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“…This is consistent with the presence of PRKA1A mutations in adrenocortical adenomas and their absence in adrenocortical cancers (16), but it is the opposite of what is observed in thyroid tumors in which PRKA1A mutations are associated with the malignant phenotype (17). This suggests that with regard to the role of PKA, diverse tumorigenic processes exist in endocrine cells of different origin.…”

Section: Discussionsupporting

confidence: 82%

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

et al. 2004

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The two regulatory subunits (R1 and R2) of protein kinase A (PKA) are differentially expressed in cancer cell lines and exert diverse roles in growth control. Recently, mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex. The aim of this study was to evaluate the expression of the PKA regulatory subunits R1A, R2A, and R2B in a series of 30 pituitary adenomas and the effects of subunit activation on cell proliferation. In these tumors, neither mutation of PRKAR1A nor loss of heterozygosity was identified. By realtime PCR, mRNA of the three subunits was detected in all of the tumors, R1A being the most represented in the majority of samples. By contrast, immunohistochemistry documented low or absent R1A levels in all tumors, whereas R2A and R2B were highly expressed, thus resulting in an unbalanced R1/R2 ratio. The low levels of R1A were, at least in part, due to proteasome-mediated degradation. The effect of the R1/R2 ratio on proliferation was assessed in GH3 cells, which showed a similar unbalanced pattern of R subunits expression, and in growth hormone-secreting adenomas. The R2-selective cAMP analog 8-Cl cAMP and R1A RNA silencing, stimulated cell proliferation and increased Cyclin D1 expression, respectively, in human and rat adenomatous somatotrophs. These data show that a low R1/R2 ratio promoted proliferation of transformed somatotrophs and are consistent with the Carney complex model in which R1A inactivating mutations further unbalance this ratio in favor of R2 subunits. These results suggest that low expression of R1A protein may favor cAMP-dependent proliferation of transformed somatotrophs.

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“…In this study, we showed that two potential target proteins, R1␣ subunit of PKA and CD52 antigen, were highly expressed in the ATRA-treated APL cells. Recently, Sandrini et al 52 reported that PKA-R1␣ acted as a tumor-suppressor gene for sporadic thyroid cancer. The administration of ATRA has been used to treat patients with APL, but ATRA alone is not necessarily sufficient to maintain patients in stable remission.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling during All-trans Retinoic Acid-Induced Cell Differentiation of Acute Promyelocytic Leukemia Cells

Yang

Zhao

et al. 2003

The Journal of Molecular Diagnostics

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Using cDNA microarrays we determined the gene expression patterns in the human acute promyelocytic leukemia (APL) cell line NB4 during all-trans retinoic acid (ATRA)-induced differentiation. We analyzed the expression of 12,288 genes in the NB4 cells after 12 hours, 24 hours, 48 hours, 72 hours, and 96 hours of ATRA exposure. During this time course, we found 168 up-regulated and more than 179 down-regulated genes, most of which have not been reported before. Many of the altered genes encode products that participate in signaling pathways, cell differentiation, programmed cell death, transcription regulation, and production of cytokines and chemokines. Of interest, the CD52 and protein kinase A regulatory subunit ␣ (PKA-Rl␣) genes, whose products are being used as therapeutic targets for certain human neoplasias in currently ongoing clinical trials, were among the genes observed to be markedly up-regulated after ATRA treatment. The present study provides valuable data to further understand the mechanism of ATRAinduced APL cell differentiation and suggests potential therapeutic alternatives for this leukemia. Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia characterized by the accumulation of cells arrested at the promyelocytic stage of myeloid differentiation. This leukemia exhibits a specific chromosomal translocation t(15;17) involving the promyelocytic leukemia (PML) gene locus on chromosome 15, and the retinoid acid receptor ␣ (RAR␣) locus on chromosome 17. This translocation generates a chimeric fusion gene PML-RAR␣, which encodes a protein that functions as an aberrant nuclear receptor considered to be the cause of APL.

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Regulatory subunit type I‐α of protein kinase A (PRKAR1A): A tumor‐suppressor gene for sporadic thyroid cancer

Cited by 83 publications

References 59 publications

Gene Expression Profiling of Differentiated Thyroid Neoplasms

Gene Expression Profiling of Differentiated Thyroid Neoplasms

Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein

Gene Expression Profiling during All-trans Retinoic Acid-Induced Cell Differentiation of Acute Promyelocytic Leukemia Cells

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