scholarly journals Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A.

1993 ◽  
Vol 13 (1) ◽  
pp. 358-366 ◽  
Author(s):  
I Bongarzone ◽  
N Monzini ◽  
M G Borrello ◽  
C Carcano ◽  
G Ferraresi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Tyrosine Kinase ◽  
Kinase Domain ◽  
Regulatory Subunit ◽  
Tyrosine Kinase Domain ◽  
Papillary Thyroid ◽  
Thyroid Carcinomas ◽  
Kinase A

The ret oncogene frequently has been found activated in papillary thyroid carcinomas. A previous characterization of ret activation revealed recombination of its tyrosine kinase domain and sequences derived from an uncharacterized locus (D10S170). The mechanism leading to this recombination was identified as a paracentric inversion of the long arm of chromosome 10, inv(10)(q11.2q21), with the breakpoints occurring where ret and D10S170 were mapped. To further characterize the activation of ret in papillary thyroid carcinomas, we have now isolated and sequenced a second type of ret oncogenic rearrangement not involving the D10S170 locus. The nucleotide sequence indicated that the transforming activity was created by the fusion of the ret tyrosine kinase domain with part of the RI alpha regulatory subunit of protein kinase A (PKA). This is the first example of an oncogenic activity involving a PKA gene. PKA is the main intracellular cyclic AMP receptor, and its RI alpha subunit gene is located on chromosome 17q. RI alpha-ret transcripts encode two isoforms of the chimeric protein (p76 and p81), which display constitutive tyrosine phosphorylation as well as a tyrosine kinase enzymatic activity. Under nonreducing conditions, both isoforms are found in a dimeric configuration because of both homo- and heterodimer formation. Thus, the in vivo activation of ret in human papillary thyroid carcinomas is provided by the fusion of its tyrosine kinase domain with different genes and can be mediated by different mechanisms of gene rearrangement.

Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A

1993 ◽  
Vol 13 (1) ◽  
pp. 358-366
Author(s):  
I Bongarzone ◽  
N Monzini ◽  
M G Borrello ◽  
C Carcano ◽  
G Ferraresi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Tyrosine Kinase ◽  
Kinase Domain ◽  
Regulatory Subunit ◽  
Tyrosine Kinase Domain ◽  
Papillary Thyroid ◽  
Thyroid Carcinomas ◽  
Kinase A

The ret oncogene frequently has been found activated in papillary thyroid carcinomas. A previous characterization of ret activation revealed recombination of its tyrosine kinase domain and sequences derived from an uncharacterized locus (D10S170). The mechanism leading to this recombination was identified as a paracentric inversion of the long arm of chromosome 10, inv(10)(q11.2q21), with the breakpoints occurring where ret and D10S170 were mapped. To further characterize the activation of ret in papillary thyroid carcinomas, we have now isolated and sequenced a second type of ret oncogenic rearrangement not involving the D10S170 locus. The nucleotide sequence indicated that the transforming activity was created by the fusion of the ret tyrosine kinase domain with part of the RI alpha regulatory subunit of protein kinase A (PKA). This is the first example of an oncogenic activity involving a PKA gene. PKA is the main intracellular cyclic AMP receptor, and its RI alpha subunit gene is located on chromosome 17q. RI alpha-ret transcripts encode two isoforms of the chimeric protein (p76 and p81), which display constitutive tyrosine phosphorylation as well as a tyrosine kinase enzymatic activity. Under nonreducing conditions, both isoforms are found in a dimeric configuration because of both homo- and heterodimer formation. Thus, the in vivo activation of ret in human papillary thyroid carcinomas is provided by the fusion of its tyrosine kinase domain with different genes and can be mediated by different mechanisms of gene rearrangement.

The Differential Response of Protein Kinase A to Cyclic AMP in Discrete Brain Areas Correlates with the Abundance of Regulatory Subunit II

2002 ◽  
Vol 66 (4) ◽  
pp. 1752-1761 ◽  
Author(s):  
Carmelo Ventra ◽  
Antonio Porcellini ◽  
Antonio Feliciello ◽  
Adriana Gallo ◽  
Mayra Paolillo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Protein Kinase A ◽  
Differential Response ◽  
Regulatory Subunit ◽  
Brain Areas ◽  
Kinase A

scholarly journals Protein Kinase A-Dependent and -Independent Signaling Pathways Contribute to Cyclic AMP-Stimulated Proliferation

1999 ◽  
Vol 19 (9) ◽  
pp. 5882-5891 ◽  
Author(s):  
Lisa A. Cass ◽  
Scott A. Summers ◽  
Gregory V. Prendergast ◽  
Jonathan M. Backer ◽  
Morris J. Birnbaum ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Dna Synthesis ◽  
Protein Kinase A ◽  
Signaling Pathways ◽  
Cell Cycle Progression ◽  
Sh2 Domain ◽  
Regulatory Subunit ◽  
Pi3k Activity ◽  
Kinase A

ABSTRACT The effects of cyclic AMP (cAMP) on cell proliferation are cell type specific. Although the growth-inhibitory effects of cAMP have been well studied, much less is known regarding how cAMP stimulates proliferation. We report that cAMP stimulates proliferation through both protein kinase A (PKA)-dependent and PKA-independent signaling pathways and that phosphatidylinositol 3-kinase (PI3K) is required for cAMP-stimulated mitogenesis. In cells where cAMP is a mitogen, cAMP-elevating agents stimulate membrane ruffling, Akt phosphorylation, and p70 ribosomal S6 protein kinase (p70s6k) activity. cAMP effects on ruffle formation and Akt were PKA independent but sensitive to wortmannin. In contrast, cAMP-stimulated p70s6k activity was repressed by PKA inhibitors but not by wortmannin or microinjection of the N-terminal SH2 domain of the p85 regulatory subunit of PI3K, indicating that p70s6k and Akt can be regulated independently. Microinjection of highly specific inhibitors of PI3K or Rac1, or treatment with the p70s6k inhibitor rapamycin, impaired cAMP-stimulated DNA synthesis, demonstrating that PKA-dependent and -independent pathways contribute to cAMP-mediated mitogenesis. Direct elevation of PI3K activity through microinjection of an antibody that stimulates PI3K activity or stable expression of membrane-localized p110 was sufficient to confer hormone-independent DNA synthesis when accompanied by elevations in p70s6k activity. These findings indicate that multiple pathways contribute to cAMP-stimulated mitogenesis, only some of which are PKA dependent. Furthermore, they demonstrate that the ability of cAMP to stimulate both p70s6k- and PI3K-dependent pathways is an important facet of cAMP-regulated cell cycle progression.

Molecular cloning and characterization of the protein kinase A regulatory subunit of Trypanosoma cruzi

2006 ◽  
Vol 149 (2) ◽  
pp. 242-245 ◽  
Author(s):  
Huan Huang ◽  
Louis M. Weiss ◽  
Fnu Nagajyothi ◽  
Herbert B. Tanowitz ◽  
Murray Wittner ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Trypanosoma Cruzi ◽  
Protein Kinase A ◽  
Molecular Cloning ◽  
Regulatory Subunit ◽  
Kinase A

scholarly journals RET protein expression has no prognostic impact on the long-term outcome of papillary thyroid carcinoma

2001 ◽  
pp. 599-604 ◽  
Author(s):  
F Basolo ◽  
E Molinaro ◽  
L Agate ◽  
A Pinchera ◽  
L Pollina ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Papillary Thyroid ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Tumor Class

BACKGROUND: RET proto-oncogene rearrangements (RET/PTC) are causative events in the pathogenesis of a subset of papillary thyroid cancer (PTC). The prevalence of RET/PTC varies in different countries and according to specific clinical features: it is higher after radiation exposure and it is claimed to be higher in young patients. Conflicting results are reported regarding the prognostic role of RET/PTC activation. OBJECTIVE: To investigate the prognostic meaning of RET/PTC rearrangement on the long term outcome of PTC. METHODS: We have studied the expression of the RET encoded protein in 127 papillary thyroid carcinomas by immunohistochemistry using a polyclonal antibody against the tyrosine-kinase domain of the RET protein. These cases have been collected during 1970-1985, and have a mean (+/-S.D.) period of follow-up of 18.6+/-3.7 years (range 12-27 years). The results have been compared with the patients' outcome. RESULTS: The tyrosine-kinase domain of RET was expressed in 82 (64.6%) papillary carcinomas. Among them, RET was highly expressed in 65 (51.2%) cases and moderately expressed in 17 (13.4%). RET expression was absent in 45 (35.4%) cases. No correlation was found between RET expression and other parameters such as sex, age at diagnosis, tumor class and histological variant. Follow-up analysis showed no influence of RET expression on patients' outcome. By multivariate analysis, age (>45 years) and tumor class IV, but not sex and RET expression were adverse prognostic indicators of death. CONCLUSION: In conclusion, our analysis indicates that RET expression is frequently found in PTC, and has no influence on tumor outcome.

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