Control of expression of the gene for the arginine transporter Cat-1 in rat liver cells by glucocorticoids and insulin

Liu, J.; Hatzoglou, Maria

doi:10.1007/bf01320897

Cited by 28 publications

(21 citation statements)

References 55 publications

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“…Among these proteins is the Cat-1 arginine/lysine transporter, which also provides cells with the substrate for NO synthesis (27). Expression of the cat-1 gene has been shown to be regulated at the transcriptional and post-transcriptional level by hormones (28,29), nutrients (2, 3) and growth factors (30,31). The translational regulation reported in this study further extends the complex regulatory mechanisms that control the cell's supply of arginine and lysine.…”

Section: Discussionsupporting

confidence: 60%

Internal Ribosome Entry Site-mediated Translation of a Mammalian mRNA Is Regulated by Amino Acid Availability

Fernandez

Yaman

Mishra

et al. 2001

Journal of Biological Chemistry

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139

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The cationic amino acid transporter, Cat-1, facilitates the uptake of the essential amino acids arginine and lysine. Amino acid starvation causes accumulation and increased translation of cat-1 mRNA, resulting in a 58-fold increase in protein levels and increased arginine uptake. A bicistronic mRNA expression system was used to demonstrate the presence of an internal ribosomal entry sequence (IRES) within the 5-untranslated region of the cat-1 mRNA. This study shows that IRES-mediated translation of the cat-1 mRNA is regulated by amino acid availability. This IRES causes an increase in translation under conditions of amino acid starvation. In contrast, cap-dependent protein synthesis is inhibited during amino acid starvation, which is well correlated with decreased phosphorylation of the cap-binding protein, eIF4E. These findings reveal a new aspect of mammalian gene expression and regulation that provides a cellular stress response; when the nutrient supply is limited, the activation of IRES-mediated translation of mammalian mRNAs results in the synthesis of proteins essential for cell survival.Amino acids are essential nutrients for cell growth and maintenance. Mammalian cells have developed an adaptive response to changes in amino acid availability (1). When the amino acid supply is limited, protein synthesis decreases, and there are increases in catabolism of cellular proteins, amino acid biosynthesis, and amino acid transport across the plasma membrane. Together these responses provide cells with amino acids needed for survival. A significant part of this adaptive response is the increased expression of the cat-1 gene, which encodes the transporter for the essential cationic amino acids, lysine and arginine (2). We have shown that the level of the Cat-1 protein and the transport of cationic amino acids increase in amino acid-depleted cells (3). Because amino acid starvation inhibits cap-dependent initiation of protein synthesis (4), we hypothesized that the cat-1 mRNA is translated in amino aciddepleted cells through a cap-independent mechanism. This translation would involve an internal ribosomal entry sequence (IRES 1 ) within the 5Ј-untranslated region (5Ј-UTR). IRES sequences have been implicated in the translation of viral mRNAs in infected cells, where cap-dependent translation of cellular mRNAs is inhibited (5). These sequences are also important in the translation of several mammalian mRNAs encoding regulatory proteins involved in growth and differentiation (6 -11). Furthermore, a role of IRES sequences in cell cycle-dependent translation of mammalian mRNAs has been demonstrated recently (6,(12)(13)(14). This study provides support for our hypothesis by demonstrating that the 5Ј-UTR of the cat-1 mRNA contains an IRES sequence. Moreover, translation from this IRES is stimulated in amino acid-starved cells, when cap-dependent translation is decreased. These findings suggest a mechanism for synthesis of proteins required for amino acid accumulation in starved cells when total protein synthesis is inhib...

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Section: Discussionsupporting

confidence: 60%

Internal Ribosome Entry Site-mediated Translation of a Mammalian mRNA Is Regulated by Amino Acid Availability

Fernandez

Yaman

Mishra

et al. 2001

Journal of Biological Chemistry

Self Cite

139

124

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“…The sequence CUUUCU within the Cat Cationic amino acid transporter 1 (Cat-1) is a high-affinity Na ϩ -independent transporter of L-arginine and L-lysine belonging to system yϩ (12, 62). Growth factors, hormones, and nutrients can modulate its expression level (20,53). Expression of the Cat-1 gene increases during stress in a manner that involves phosphorylation of translation initiation factor 2␣ (eIF2␣) (24).…”

mentioning

confidence: 99%

“…Growth factors, hormones, and nutrients can modulate its expression level (20,53). Expression of the Cat-1 gene increases during stress in a manner that involves phosphorylation of translation initiation factor 2␣ (eIF2␣) (24).…”

mentioning

confidence: 99%

The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation

Majumder

Yaman

Gaccioli

et al. 2009

Molecular and Cellular Biology

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The response to amino acid starvation involves the global decrease of protein synthesis and an increase in the translation of some mRNAs that contain an internal ribosome entry site (IRES). It was previously shown that translation of the mRNA for the arginine/lysine amino acid transporter Cat-1 increases during amino acid starvation via a mechanism that utilizes an IRES in the 5 untranslated region of the Cat-1 mRNA. It is shown here that polypyrimidine tract binding protein (PTB) and an hnRNA binding protein, heterogeneous nuclear ribonucleoprotein L (hnRNP L), promote the efficient translation of Cat-1 mRNA during amino acid starvation. Association of both proteins with Cat-1 mRNA increased during starvation with kinetics that paralleled that of IRES activation, although the levels and subcellular distribution of the proteins were unchanged. The sequence CUUUCU within the Cat Cationic amino acid transporter 1 (Cat-1) is a high-affinity Na ϩ -independent transporter of L-arginine and L-lysine belonging to system yϩ (12, 62). Growth factors, hormones, and nutrients can modulate its expression level (20,53). Expression of the Cat-1 gene increases during stress in a manner that involves phosphorylation of translation initiation factor 2␣ (eIF2␣) (24). During such conditions, expression of the Cat-1 gene is regulated at the level of (i) mRNA synthesis via the transcription factor ATF4, which binds an amino acid response element in the first exon of the gene (54); (ii) mRNA stability via the binding of the nucleocytoplasmic protein HuR to an AU-rich element present within its 3Ј untranslated region (UTR) (94); and (iii) translation via a cap-independent mechanism of initiation via an internal ribosome entry site (IRES) (23).IRES-dependent translation involves the recruitment of ribosomes independently of the m 7 G cap at the 5Ј end of the mRNA followed by initiation downstream of the ribosome binding site (46). We showed that increased translation of the Cat-1 mRNA during amino acid starvation requires the translation of a 48-amino-acid open reading frame (ORF) in the 5Ј UTR of the mRNA, introducing the concept of a "dynamic IRES" (23,93). In the absence of upstream ORF (uORF) translation, the Cat-1 IRES remains in an inactive conformation. During starvation, translation of the uORF unwinds this secondary structure, leading to formation of a conformation that has IRES activity. Previous studies have also proposed that the active conformation is stabilized by proteins (IRES transactivating factors [ITAFs]) that are either synthesized or modified by processes that require eIF2␣ phosphorylation. We also showed that decreased translation elongation rates of the uORF in fed cells result in a prolonged half-life of this active remodeled structure, mimicking the role of ITAFs in amino acid-starved cells (21). Ribosome stalling within the uORF can occur physiologically during stresses that cause increased phosphorylation of elongation factor 2 and therefore decreased translation elongation rates (63). These two mechanisms o...

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“…In this scenario, insulin reduces protein catabolism [26], affects the cationic amino acid y+ transport system and may thereby increase the uptake of ADMA in organs able to eliminate it [27,28,30,31]. Insulin may also preserve dimethylarginine-hydrolase inhibition due to hyperglycemia [29].…”

Section: Discussionmentioning

confidence: 99%

Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients

et al. 2008

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Objective: We investigated whether preventing hyperglycemia in septic patients affected the plasma concentration of asymmetric-dimethylarginine and if this was associated with clinical benefit. Design: A prospective, multicenter, randomized, controlled, clinical study. Setting: Intensive care units (ICU) in three university hospitals. Patients: A total of 72 patients admitted for severe sepsis or septic shock, who stayed at least 3 days in the ICU. At admission the patients were assigned to receive either tight or conventional glycemic control. Interventions: Determination of circulating levels of asymmetric-dimethylarginine, arginine, interleukin-6, C-reactive-protein and tumor-necrosis-factor-a. Measurements and results: Blood was sampled at admission (no differences between groups), and on the 3rd, 6th, 9th, and 12th (T12) days. Sequential organ failure assessment was scored at each sampling time. All the data were analyzed on an intention-to-treat basis. The control and treatment groups received the same energy intake, glycemia (110.4 ± 17.3 vs. 163.0 ± 28.9 mg/dL, P \ 0.001) and insulin (P = 0.02) supply differed. No differences were found in high plasma levels of asymmetricdimethylarginine (P = 0.812) at any time during the ICU stay. The clinical course, as indicated by markers of inflammation, average and maximum organ failure score, ICU stay and ICU and 90-day mortality, was the same. Conclusions: Intensive insulin treatment, while achieving glucose control, did not reduce asymmetricdimethylarginine in high-risk septic patients fed with no more than 25 kcal/kg per day to limit ventilatory demand and to simplify glucose control. Descriptor: 45 (SIRS/sepsis: clinical studies).

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Control of expression of the gene for the arginine transporter Cat-1 in rat liver cells by glucocorticoids and insulin

Cited by 28 publications

References 55 publications

Internal Ribosome Entry Site-mediated Translation of a Mammalian mRNA Is Regulated by Amino Acid Availability

Internal Ribosome Entry Site-mediated Translation of a Mammalian mRNA Is Regulated by Amino Acid Availability

The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation

Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients

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