Tumor reversion: protein kinase A isozyme switching.
The regulatory subunit of cAMP-dependent protein kinase (PKA) exists in the isoforms RI and RII, which distinguish PKA isozymes type I (PKA-I) and type II (PKA-II). Evidence obtained from different experimental approaches-such as site-selective cAMP analogs, antisense oligonucleotides, transcription factor decoys, cDNA microarrays, and gene transfer-has shown that PKA-I and -II are expressed in a balance of cell growth and differentiation. Loss of this balance may underlie cancer genesis and progression. DNA microarrays demonstrate that antisense suppression of the RIalpha, which upregulates RIIbeta, downregulates a wide range of genes involved in cell proliferation and transformation while upregulating cell differentiation and reverse transformation genes in PC3M prostate tumors that undergo regression. Conversely, the vector-mediated overexpression of RIIbeta, as opposed to those of RIalpha and Calpha, exhibits induction of differentiation genes along with suppression of cell proliferation and transformation genes leading to reversion of tumor phenotype. Thus, switching of PKA isozyme can cause tumor cells to undergo phenotypic reversion of the malignancy.
Cho-Chung
Yoon S
YS
Cellular Biochemistry Section, Basic Research Laboratory, National Cancer Institute, Building 10, Room 5B05, 9000 Rockville Pike, Bethesda, MD 20892-1750, USA. yc12b@nih.gov
Nesterova
Maria V
MV
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010641:Phenotype; D020033:Protein Isoforms
D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases