Background Most cells possess a sophisticated mechanism for sensing glucose and responsing to it appropriately. Glucose sensing and signaling in the budding yeast Saccharomyces cerevisiae represents an important paradigm for understanding how extracellular signals lead to changes in the gene expression program in eukaryotes. Scope of review This review focuses on the yeast glucose sensing and signaling pathways that operate in a highly regulated and cooperative manner to bring about glucose-induction of HXT gene expression. Major conclusions The yeast cells possess a family of glucose transporters (HXTs), with different kinetic properties. They employ three major glucose signaling pathways— Rgt2/Snf3, AMPK, and cAMP-PKA—to express only those transporters best suited for the amounts of glucose available. We discuss the current understanding of how these pathways are integrated into a regulatory network to ensure efficient uptake and utilization of glucose. General significance Elucidating the role of multiple glucose signals and pathways involved in glucose uptake and metabolism in yeast may reveal the molecular basis of glucose homeostasis in humans, especially under pathological conditions, such as hyperglycemia in diabetics and the elevated rate of glycolysis observed in many solid tumors.

Protein kinase D is a family of evolutionarily conserved serine/threonine kinases that belongs to the Ca++/Calmodulin-dependent kinase superfamily. Signal transduction pathways mediated by PKD can be triggered by a variety of stimuli including G protein-coupled receptor agonists, growth factors, hormones, and cellular stresses. The regulatory mechanisms and physiological roles of PKD have been well documented including cell proliferation, survival, migration, angiogenesis, regulation of gene expression, and protein/membrane trafficking. However, its precise roles in disease progression, especially in cancer, remain elusive. A plethora of studies documented the cell- and tissue-specific expressions and functions of PKD in various cancer-associated biological processes, while the causes of the differential effects of PKD have not been thoroughly investigated. In this review, we have discussed the structural-functional properties, activation mechanisms, signaling pathways and physiological functions of PKD in the context of human cancer. Additionally, we have provided a comprehensive review of the reported tumor promoting or tumor suppressive functions of PKD in several major cancers types and discussed the discrepancies that have been raised on PKD as a major regulator of malignant transformation.

Background The budding yeast S. cerevisiae possesses multiple glucose transporters with different affinities for glucose that enable it to respond to a wide range of glucose concentrations. The steady-state levels of glucose transporters are regulated in response to changes in the availability of glucose. This study investigates the glucose regulation of the low affinity, high capacity glucose transporter Hxt1. Methods and results Western blotting and confocal microscopy were performed to evaluate glucose regulation of the stability of Hxt1. Our results show that glucose starvation induces endocytosis and degradation of Hxt1 and that this event requires End3, a protein required for endocytosis, and the Doa4 deubiquitination enzyme. Mutational analysis of the lysine residues in the Hxt1 N-terminal domain demonstrates that the two lysine residues, K12 and K39, serve as the putative ubiquitin-acceptor sites by the Rsp5 ubiquitin ligase. We also demonstrate that inactivation of PKA (cAMP-dependent protein kinase A) is needed for Hxt1 turnover, implicating the role of the Ras/cAMP-PKA glucose signaling pathway in the stability of Hxt1. Conclusion and general significance Hxt1, most useful when glucose is abundant, is internalized and degraded when glucose becomes depleted. Of note, the stability of Hxt1 is regulated by PKA, known as a positive regulator for glucose induction of HXT1 gene expression, demonstrating a dual role of PKA in regulation of Hxt1.

The yeast glucose transporter gene (HXT) repressor Rgt1 recruits the general corepressor complex Ssn6-Tup1 to bring about repression. The glucose-responsive transcription factor Mth1 is a transcriptional corepressor that mediates the interaction of Rgt1 with Ssn6-Tup1 by blocking the PKA-dependent phosphorylation of Rgt1.

The yeast Rgt1 repressor is a bifunctional protein that acts as a transcriptional repressor and activator. Under glucose-limited conditions, Rgt1 induces transcriptional repression by forming a repressive complex with its corepressors Mth1 and Std1. Here, we show that Rgt1 is converted from a transcriptional repressor into an activator under high glucose conditions and this occurs through two independent but consecutive events mediated by two glucose signaling pathways: (1) disruption of the repressive complex by the Rgt2/Snf3 pathway; (2) phosphorylation of Rgt1 by the cAMP-PKA (cAMP-dependent protein kinase) pathway. Rgt1 is phosphorylated by PKA at four serine residues within its amino-terminal region, but this does not occur until the repressive complex is disrupted. While phosphorylation of any one of these sites is sufficient to enable Rgt1 to induce transcriptional activation, phosphorylation of all the sites results in the release of Rgt1 from DNA. We discuss how the bifunctional properties of Rgt1 are regulated through differential phosphorylation.

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) has long been implicated in neuronal injury caused by acute ischemia/ reperfusion (I/R). However, its precise role and regulatory mechanisms remain obscure. Here, we investigated the role of the CaMKII family in neuronal survival during I/R. Our data indicated that CAMK2D/CaMKIIδ and CAMK2G/CaMKIIγ were selectively upregulated in a time-dependent manner at both transcriptional and protein levels after acute ischemia. Overexpression of CaMKIIδ promoted neuronal survival, while their depletion exacerbated ischemic neuronal death. Similar to CaMKIIδ, knockdown of CAMKIIγ resulted in significant neuronal death after I/R. We further identified CaMKIIδ 2 as the subtype that is selectively induced by I/R in primary neurons. The induction of CaMKIIδ was controlled in part by a pair of long non-coding RNAs (lncRNAs), C2dat1 and C2dat2. C2dat2, similar to C2dat1, was upregulated by I/R and cooperated with C2dat1 to modulate CaMKIIδ expression. Knockdown of C2dat1/2 blocked OGD/R-induced CaMKIIδ expression and decreased neuronal survival but did not affect the levels of CaMKIIγ, indicating specific targeting of CAMK2D by C2dat1/2. Mechanistically, I/R-induced CaMKIIδ and CaMKIIγ caused the upregulation of IKKα/β and further activation of the NF-κB signaling pathway to protect neurons from ischemic damage. Genetically, downregulating p65 subunit of NF-κB in mice increased I/R-induced neuronal death by blocking the activity of CaMKII/IKK/IκBα/NF-κB signaling axis. In summary, CaMKIIδ and CaMKIIγ are novel I/R-induced genes that promote neuronal survival during ischemic injury. The upregulation of these CaMKII kinases led to activation of the NF-κB signaling pathway, which protects neurons from ischemic damage.

The yeast Rgt1 repressor inhibits transcription of the glucose transporter (HXT) genes in the absence of glucose. It does so by recruiting the general corepressor complex Ssn6-Tup1 and the HXT corepressor Mth1. In the presence of glucose, Rgt1 is phosphorylated by the cAMP-activated protein kinase A (PKA) and dissociates from the HXT promoters, resulting in expression of HXT genes. In this study, using Rgt1 chimeras that bind DNA constitutively, we investigate how glucose regulates Rgt1 function. Our results show that the DNA-bound Rgt1 constructs repress expression of the HXT1 gene in conjunction with Ssn6-Tup1 and Mth1, and that this repression is lifted when they dissociate from Ssn6-Tup1 in high glucose conditions. Mth1 mediates the interaction between the Rgt1 constructs and Ssn6-Tup1, and glucose-induced downregulation of Mth1 enables PKA to phosphorylate the Rgt1 constructs. This phosphorylation induces dissociation of Ssn6-Tup1 from the DNA-bound Rgt1 constructs, resulting in derepression of HXT gene expression. Therefore, Rgt1 removal from DNA occurs in response to glucose but is not necessary for glucose induction of HXT gene expression, suggesting that glucose regulates Rgt1 function by primarily modulating the Rgt1 interaction with Ssn6-Tup1.

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