Regulation of Drosophila Tracheal System Development by Protein Kinase B

Jin, Jing; Anthopoulos, Norman; Wetsch, Benjamin; Binari, Richard; Isaac, Daniel D.; Andrew, Deborah J.; Woodgett, James R.; Manoukian, Armen S.

doi:10.1016/s1534-5807(01)00090-9

Cited by 36 publications

(31 citation statements)

References 43 publications

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“…This mechanism might certainly contribute to the regulation of members of the family that are controlled by external stimuli, such as the mammalian Ahr, which is activated by xenobiotic ligands (41), or Sima, which mediates adaptation to environmental oxygen tension. Interestingly, subcellular localization of the master regulator of tracheal development, Trachealess, which is not primarily involved in adaptation to environmental stimuli, has been reported to be regulated by the activity of the phosphatidylinositol 3-kinase/Akt pathway (22). Thus, it is conceivable that other bHLH-PAS members, such as the circadian protein Cycle or other bHLH-PAS proteins primarily involved in developmental processes, such as Single minded and Dysfusion, might be subjected to regulation of subcellular localization as well.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Drosophila Hypoxia-Inducible Factor α Sima by CRM1-Dependent Nuclear Export

Romero

Irisarri

Roth

et al. 2008

Molecular and Cellular Biology

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Hypoxia-inducible factor ␣ (HIF-␣) proteins are regulated by oxygen levels through several different mechanisms that include protein stability, transcriptional coactivator recruitment, and subcellular localization. It was previously reported that these transcription factors are mainly nuclear in hypoxia and cytoplasmic in normoxia, but so far the molecular basis of this regulation is unclear. We show here that the Drosophila melanogaster HIF-␣ protein Sima shuttles continuously between the nucleus and the cytoplasm. We identified the relevant nuclear localization signal and two functional nuclear export signals (NESs). These NESs are in the Sima basic helix-loop-helix (bHLH) domain and promote CRM1-dependent nuclear export. Site-directed mutagenesis of either NES provoked Sima nuclear retention and increased transcriptional activity, suggesting that nuclear export contributes to Sima regulation. The identified NESs are conserved and probably functional in the bHLH domains of several bHLH-PAS proteins. We propose that rapid nuclear export of Sima regulates the duration of cellular responses to hypoxia.In eukaryotic organisms, transcription factors are typically regulated at the level of transcription or controlled through a wide variety of posttranslational mechanisms that frequently operate simultaneously to cope with dynamic cell needs. Regulation of transcription factor expression is a robust mechanism, usually associated with highly stereotyped processes, such as the development of multicellular organisms. Regulation through posttranslational modifications, such as phosphorylation, proteolytic processing, and control of subcellular localization, is less robust but allows for rapid responses that enable adaptation to external insults or modifications in the extracellular milieu. Therefore, the combination of transcriptional and posttranslational mechanisms that account for transcription factor regulation ensures an ample repertoire of responses that allows adaptation to diverse situations.

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Section: Discussionmentioning

confidence: 99%

Regulation of the Drosophila Hypoxia-Inducible Factor α Sima by CRM1-Dependent Nuclear Export

Romero

Irisarri

Roth

et al. 2008

Molecular and Cellular Biology

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“…These mechanisms include (i) competition between Dys and Trh for dimerization with Tgo, (ii) competitive Dys: Tgo binding to Trh:Tgo autoregulatory binding sites in the trh gene, (iii) activation of genes by Dys that encode proteins influencing trh RNA or protein stability, and (iv) inhibition of protein kinase B that is required for Trh nuclear transport (19). Conceptually, the first model is the simplest and most attractive.…”

Section: Discussionmentioning

confidence: 99%

The Drosophila dysfusion Basic Helix-Loop-Helix (bHLH)–PAS Gene Controls Tracheal Fusion and Levels of the Trachealess bHLH-PAS Protein

Jiang

Crews

2003

Molecular and Cellular Biology

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The development of the mature insect trachea requires a complex series of cellular events, including tracheal cell specification, cell migration, tubule branching, and tubule fusion. Here we describe the identification of the Drosophila melanogaster dysfusion gene, which encodes a novel basic helix-loop-helix (bHLH)-PAS protein conserved between Caenorhabditis elegans, insects, and humans, and controls tracheal fusion events. The Dysfusion protein functions as a heterodimer with the Tango bHLH-PAS protein in vivo to form a putative DNA-binding complex. The dysfusion gene is expressed in a variety of embryonic cell types, including trachealfusion, leading-edge, foregut atrium cells, nervous system, hindgut, and anal pad cells. RNAi experiments indicate that dysfusion is required for dorsal branch, lateral trunk, and ganglionic branch fusion but not for fusion of the dorsal trunk. The escargot gene, which is also expressed in fusion cells and is required for tracheal fusion, precedes dysfusion expression. Analysis of escargot mutants indicates a complex pattern of dysfusion regulation, such that dysfusion expression is dependent on escargot in the dorsal and ganglionic branches but not the dorsal trunk. Early in tracheal development, the Trachealess bHLH-PAS protein is present at uniformly high levels in all tracheal cells, but since the levels of Dysfusion rise in wild-type fusion cells, the levels of Trachealess in fusion cells decline. The downregulation of Trachealess is dependent on dysfusion function. These results suggest the possibility that competitive interactions between basic helix-loop-helix-PAS proteins (Dysfusion, Trachealess, and possibly Similar) may be important for the proper development of the trachea.The insect tracheal system consists of an intricately branched system of tubules that provide oxygen throughout the animal. The formation of the trachea consists of a series of developmental events, and its analysis provides an excellent model system for studying the morphogenesis of other branched structures, such as the vertebrate lung airways, circulatory system, kidney ducts, and excretory epithelia (9, 27, 38). The trachea is derived from an array of segmentally repeated clusters of precursor cells. After the tracheal precursor cells divide and invaginate, they extend branches, and the branches from neighboring segments fuse to form the mature tracheal tree. The fusion process is mediated by a distinct fusion cell residing on each branch (41). Branching and fusion are complex cellular processes and pose a number of developmental questions. How are fusion cells specified during tracheal development? What are the short-range and long-range factors that guide tracheal branches to their fusion partners? What is the nature of the adhesive and contact-guidance interactions that mediate fusion and allow the formation of adherens junctions that seal intercellular junctions? How is the cytoskeleton rearranged to allow the tracheal lumen to extend throughout the branch?The tracheal primordia extend bra...

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“…Transfections were performed using Lipofectamine 2000 reagent (Invitrogen) following the manufacturer's instructions. Drosophila Schneider Line-2 cells (S2) expressing stable Dp110 KD and CAAXbox fusion were described previously (Jin et al, 2001). To isolate stable expressing clonal cell lines, 293 cells transfected with myr-ER-FLAG-PKB or ER-FLAG constructs selected in G418-containing medium.…”

Section: Dna Plasmids and Reagentsmentioning

confidence: 99%

Chronic activation of protein kinase Bβ/Akt2 leads to multinucleation and cell fusion in human epithelial kidney cells: events associated with tumorigenesis

Jin

Woodgett

2005

Oncogene

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Regulation of Drosophila Tracheal System Development by Protein Kinase B

Cited by 36 publications

References 43 publications

Regulation of the Drosophila Hypoxia-Inducible Factor α Sima by CRM1-Dependent Nuclear Export

Regulation of the Drosophila Hypoxia-Inducible Factor α Sima by CRM1-Dependent Nuclear Export

The Drosophila dysfusion Basic Helix-Loop-Helix (bHLH)–PAS Gene Controls Tracheal Fusion and Levels of the Trachealess bHLH-PAS Protein

Chronic activation of protein kinase Bβ/Akt2 leads to multinucleation and cell fusion in human epithelial kidney cells: events associated with tumorigenesis

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