Lactate dehydrogenase A subunit messenger RNA stability is synergistically regulated via the protein kinase A and C signal transduction pathways.

Huang, Delai; Hubbard, Christopher; Jungmann, Richard A.

doi:10.1210/mend.9.8.7476996

Cited by 16 publications

(32 citation statements)

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“…Although it is known that increased levels of either cAMP or phorbol ester are sufficient signals for increased LDH-A mRNA stability, the molecular mechanisms mediating the effects of cAMP or phorbol ester on mRNA stability have not been defined in detail. Based on our previous data (4, 12), we suggested that sequences within the non-coding regions of LDH-A mRNA together with protein kinase-regulated RNA-binding phosphoprotein(s) may play a pivotal role in determining the basal and regulated stability of mRNA (12,22).In the present study, we have chosen to identify putative cis-regulatory domains within the 3Ј-UTR of LDH-A mRNA that are involved in protein kinases A-mediated mRNA stability regulation. Our initial approach was to express transfected chimeric ␤-globin/ldh 3Ј-UTR constructs and to evaluate the functional effects of protein kinase A on chimeric mRNA stability.…”

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confidence: 95%

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confidence: 96%

“…Investigations into the mechanism of LDH-A gene expression has identified two basic controls consisting of a transcription-regulatory cascade (4,6,11) and a mechanism that regulates the half-life of LDH-A mRNA (4,12), both of which are major determinants of intracellular LDH-A mRNA levels.…”

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Protein Kinase A-regulated Instability Site in the 3′-Untranslated Region of Lactate Dehydrogenase-A Subunit mRNA

Tian

Huang

Short

et al. 1998

Journal of Biological Chemistry

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Expression of the lactate dehydrogenase A subunit (LDH-A) gene can be controlled by transcriptional as well as posttranscriptional mechanisms. In rat C6 glioma cells, LDH-A mRNA is stabilized by activation and synergistic interaction of protein kinases A and C. In the present study, we aimed to identify the sequence domain which determines and regulates mRNA stability/ instability by protein kinase A and focused our attention on the 3-untranslated region (3-UTR) of LDH-A mRNA. We have constructed various chimeric globin/ lactate dehydrogenase (ldh) genes linked to the c-fos promoter and stably transfected them into rat C6 glioma cells. After their transfection, we determined the halflife of transcribed chimeric globin/ldh mRNAs. The results showed that at least three sequence domains within the LDH- Analysis of the LDH 1 isoenzyme patterns in various cell types under a variety of physiologic conditions suggests complex regulatory mechanisms that determine specific isoenzyme expression (1-7). The LDH-A subunit, for instance, is subject to regulation by a number of different effector agents such as estrogen (3,8), epidermal growth factor (5), catecholamines (4, 9), phorbol ester (7), and c-Myc (10), which change the isoenzyme pattern almost exclusively in favor of the LDH-5 (A4) isoenzyme. The functional importance of these LDH isoenzyme shifts is generally attributed to a need for increased A subunitcontaining isoforms (such as LDH-4 or -5), which can derive more energy from the anaerobic pathway by reducing pyruvate to lactate. Investigations into the mechanism of LDH-A gene expression has identified two basic controls consisting of a transcription-regulatory cascade (4, 6, 11) and a mechanism that regulates the half-life of LDH-A mRNA (4, 12), both of which are major determinants of intracellular LDH-A mRNA levels.Messenger RNA turnover rates fluctuate over a wide range, and it is important to identify and characterize putative stability-regulating mRNA domains and their interacting factors that may be responsible for these functional effects. A great number of reports have demonstrated the existence of such domains and their trans-acting regulatory factors that are critical in determining the half-life of mRNA (13). Several of these studies indicate that the stability of some, but not all, mRNA is determined by specific cis-acting AU-rich domains located in the 3Ј-UTR. For example, a number of mRNAs such as cytokine, lymphokine and protooncogene mRNAs share a common sequence motif with a high content of A and U nucleotides in the 3Ј-UTR (14) and exhibit half-lives in the range of only a fraction of 1 h (15-18). In addition, attention has focused on modulation of mRNA stability in response to a variety of physiological signals. For instance, histone mRNA stability is regulated by the cell cycle (19) and intracellular iron levels control the stability of transferrin receptor mRNA (20,21). Moreover, manipulation of cells with several different effector agents can alter the steady-state level of mRNA during cell g...

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Protein Kinase A-regulated Instability Site in the 3′-Untranslated Region of Lactate Dehydrogenase-A Subunit mRNA

Tian

Huang

Short

et al. 1998

Journal of Biological Chemistry

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“…The intracellular level of LDH-A mRNA, however, does not entirely reflect the effector agentinduced increased rate of gene transcription (1), implying that its steady-state level is concomitantly regulated by the ability of cells to modulate LDH-A mRNA stability. Indeed, the relatively short half-life LDH-A mRNA (t1 ⁄2 Ϸ 55 min) increases markedly in response to activators of the PKA signal transduction pathway (1,4,6,7). As a consequence, the cellular isoenzyme pattern is shifted in favor of LDH-5 altering the aerobic/ anaerobic metabolic status of cells.…”

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Cyclic AMP and AKAP-mediated Targeting of Protein Kinase A Regulates Lactate Dehydrogenase Subunit A mRNA Stability

Jungmann

Kiryukhina

2005

Journal of Biological Chemistry

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Expression of the lactate dehydrogenase A subunit (ldh-AHowever, the mechanistic details of interaction of CSR with proteins as they pertain to mRNA stabilization by PKA are so far largely unknown. In this study we tested the hypothesis that ribosomal protein extracts (RSW) from glioma cells contain PKA regulatory (RII) and catalytic (C) subunits that, in combination with a protein kinase A anchoring protein (AKAP 95) and CSRBPs participate in forming CSR-protein complexes that are responsible for mRNA stability regulation. To demonstrate the importance of CSR-protein complex formation, the PKA subunits and AKAP 95 were removed from the RSW by immunoprecipitation, and the antigen-deleted RSW were subjected to CSR binding analysis using gel mobility shift and UV cross-linking. It was shown that AKAP 95 as well as RII formed a direct linkage with CSR during CSR-protein complex formation. In contrast, the catalytic subunit formed part of the CSR-protein complex but did not bind to CSR directly in a covalent linkage. To determine whether formation of CSR complexes that included C, RII, and AKAP 95 constituted a functional event and was necessary for mRNA stabilization, cell-free decay reactions were carried out with RSW extracts, and the kinetics of decay of LDH-A mRNA was determined. Depletion of PKA subunits and AKAP 95 from RSW extracts by immunoprecipitation resulted in a marked loss of mRNA stabilization activity indicating that the presence of the PKA regulatory and catalytic subunits as well as AKAP 95 in the CSR-protein complexes was absolutely necessary to achieve LDH-A mRNA stabilization.

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“…Increments in LDH A mRNA levels may be related to increased transcription of ldh a gene. However, considering that Huang et al (1995) have shown that pkC -a signal transduction pathway that may be utilized by bFGF -plays an active functional role in regulating LDH A mRNA stability in rat C6 glioma cells, an mRNA stabilizing mechanism cannot be ruled out. Thus, the possibility exists that, in rat Sertoli cells, bFGF controls the expression of the LDH subunit A at a transcriptional and/or post-transcriptional level.…”

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confidence: 99%

Regulation of lactate production and glucose transport as well as of glucose transporter 1 and lactate dehydrogenase A mRNA levels by basic fibroblast growth factor in rat Sertoli cells

Riera

Meroni²,

Schteingart³

et al. 2002

Journal of Endocrinology

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By using cultured rat Sertoli cells as a model, both the action of basic fibroblast growth factor (bFGF) on lactate production and the site of this action were studied. bFGF stimulated Sertoli cell lactate production in a dosedependent manner (basal: 7·3 0·5; 0·1 ng/ml bFGF: 7·5 0·5; 1 ng/ml bFGF: 7·5 0·6; 10 ng/ml bFGF: 10·3 1·0; 30 ng/ml bFGF: 15·2 1·5; 50 ng/ml bFGF: 15·4 1·6 µg/µg DNA). Two major sites for the action of this growth factor were identified. First, bFGF was shown to exert short-and long-term stimulatory effects on glucose transport (basal: 1170 102; 30 ng/ml bFGF for 120 min: 1718 152 and basal: 718 64; 30 ng/ml bFGF for 48 h: 1069 69 d.p.m./µg DNA respectively). Short-term bFGF stimulation of glucose transport was not inhibited by the protein synthesis inhibitor cycloheximide. These results indicate that short-term bFGF stimulation of glucose uptake does not involve an increase in the number of glucose transporters. On the other hand, stimulation with bFGF for periods of time longer than 12 h increased glucose transporter 1 (GLUT1) mRNA levels. These increased mRNA levels were probably ultimately responsible for the increments in glucose uptake that are observed in long-term treated cultures. Secondly, bFGF increased lactate dehydrogenase (LDH) activity (basal: 31·0 1·4; 30 ng/ml bFGF: 45·7 2·4 mIU/µg DNA). The principal subunit component of those LDH isozymes that favors the transformation of pyruvate to lactate is subunit A. bFGF increased LDH A mRNA levels in a dose-and time-dependent manner. In summary, the results presented herein show that glucose transport, LDH activity and GLUT1 and LDH A mRNA levels are regulated by bFGF to achieve an increase in lactate production. These observed regulatory actions provide unequivocal evidence of the participation of bFGF in Sertoli cell lactate production which may be related to normal germ cell development.

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Lactate dehydrogenase A subunit messenger RNA stability is synergistically regulated via the protein kinase A and C signal transduction pathways.

Cited by 16 publications

References 41 publications

Protein Kinase A-regulated Instability Site in the 3′-Untranslated Region of Lactate Dehydrogenase-A Subunit mRNA

Protein Kinase A-regulated Instability Site in the 3′-Untranslated Region of Lactate Dehydrogenase-A Subunit mRNA

Cyclic AMP and AKAP-mediated Targeting of Protein Kinase A Regulates Lactate Dehydrogenase Subunit A mRNA Stability

Regulation of lactate production and glucose transport as well as of glucose transporter 1 and lactate dehydrogenase A mRNA levels by basic fibroblast growth factor in rat Sertoli cells

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