Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progression through the cell cycle depends on sequential activation of Cyclin-Dependent Kinase(s). In this report we use budding-yeast meiosis as a tool to elucidate the specific functions of mammalian Cdks. Yeast meiosis is regulated by both Cdc28 (yCdk1) and Ime2 (a meiosis-specific Cdk-like kinase). We show that human Cdk2 is a functional homolog for most of Ime2 functions. It promotes efficient and timely entry into premeiotic DNA replication and the first nuclear division, as well as the regulated transcription of IME1 and the early meiosis-specific genes. We show that this effect is specific, and that neither mice Cdk1, nor mice Cdk4 can suppress ime2. We show that Cdk1 is a functional homolog of Cdc28 that also suppresses one of its meiotic functions, namely inhibiting the transcription of IME1. Cdk2, on the other hand, show dominant negative effects on entry into the cell cycle, most probably by inhibiting the function of Cdc28. Finally, we show that in the meiotic pathway Cdk4 functions as a transcriptional activator.
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PMID:Human Cdk2 is a functional homolog of budding yeast Ime2, the meiosis-specific Cdk-like kinase. 1922 73

Autophagy is the major cellular pathway by which macromolecules are degraded, and amino acid depletion powerfully activates autophagy. MAP4K3, or germinal-center kinase-like kinase, is required for robust cell growth in response to amino acids, but the basis for MAP4K3 regulation of cellular metabolic disposition remains unknown. Here we identify MAP4K3 as an amino acid-dependent regulator of autophagy through its phosphorylation of transcription factor EB (TFEB), a transcriptional activator of autophagy, and through amino acid starvation-dependent lysosomal localization of MAP4K3. We document that MAP4K3 physically interacts with TFEB and MAP4K3 inhibition is sufficient for TFEB nuclear localization, target gene transactivation, and autophagy, even when mTORC1 is activated. Moreover, MAP4K3 serine 3 phosphorylation of TFEB is required for TFEB interaction with mTORC1-Rag GTPase-Ragulator complex and TFEB cytosolic sequestration. Our results uncover a role for MAP4K3 in the control of autophagy and reveal MAP4K3 as a central node in nutrient-sensing regulation.
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PMID:MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB. 2950 40

The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington's disease could render the striatum highly vulnerable to neurodegeneration.
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PMID:The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin. 2953 57