The Oncogene PDRG1 Is an Interaction Target of Methionine Adenosyltransferases

Abstract

Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high Vmax (MAT III) isoenzymes, whereas the low Vmax (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has been scarcely studied. Using yeast two hybrid and a rat liver library we identified PDRG1 as an interaction target for MATα1 (catalytic subunit of MAT I and MAT III), further confirmation being obtained by immunoprecipitation and pull-down assays. Nuclear MATα interacts physically and functionally with the PDRG1 oncogene, resulting in reduced DNA methylation levels. Increased Pdrg1 expression is detected in acute liver injury and hepatoma cells, together with decreased Mat1a expression and nuclear accumulation of MATα1. Silencing of Pdrg1 expression in hepatoma cells alters their steady-state expression profile on microarrays, downregulating genes associated with tumor progression according to GO pathway analysis. Altogether, the results unveil the role of PDRG1 in the control of the nuclear methylation status through methionine adenosyltransferase binding and its putative collaboration in the progression of hepatic diseases.

Methionine Adenosyltransferase α1 Is Targeted to the Mitochondrial Matrix and Interacts with Cytochrome P450 2E1 to Lower Its Expression

“…Much of the phenotype of Mat1a KO mice was thought to be consequences of cytosolic SAM deficiency, although how SAM deficiency resulted in increased CYP2E1 expression was unclear. More recently, our study and others have shown that MATα1 can target the nuclear compartment where it can regulate gene expression by epigenetic mechanisms . In addition, we recently showed that MATα1 interacts directly with MAX and c‐MYC and negatively regulates E‐box‐driven reporter activity .…”

“…More recently, our study and others have shown that MATα1 can target the nuclear compartment where it can regulate gene expression by epigenetic mechanisms. (26)(27)(28) In addition, we recently showed that MATα1 interacts directly with MAX and c-MYC and negatively regulates E-box-driven reporter activity. (19) This prompted us to investigate the MATα1 interactome, which revealed the unexpected high number of mitochondrial proteins, FIg.…”

High-throughput profiling of diapause regulated genes from Trichogramma dendrolimi, an important egg parasitoid

“…In Artemia sinica, PDRG1 takes an essential role in diapause termination and regulation of cell cycle during early embryonic development [44] . By blocking the expression of pdrg1 in human colon cancer cells, cell growth reduced significantly [45] . Transcriptome based analysis indicated that the expression of p53 was significantly increased during diapause, and the contrary result was observed for pdrg1 in T.…”

Methionine adenosyltransferases in liver health and diseases

“…12 Monomeric MATα1 is also found in nuclei and may be involved in other interactions. 12,13 Both MATα2 and MATβ subunits of the MATII isoenzyme have been detected in the cytoplasm and nucleus of mammalian cells. 14 Distinct functional interactions of these proteins exist based on their subcellular localization.…”

“…13 PDRG1 is an oncogene that is upregulated in cancers of the bladder, breast, and colon. 77 When PDGR1 binds to nuclear MATα1 there was a decrease in MAT activity and DNA was hypomethylated.…”