Bunched, the Drosophila homolog of the mammalian tumor suppressor TSC-22, promotes cellular growth

<p>Abstract</p> <p>Background</p> <p>Transforming Growth Factor-β1 stimulated clone-22 (TSC-22) is assumed to act as a negative growth regulator and tumor suppressor. TSC-22 belongs to a family of putative transcription factors encoded by four distinct loci in mammals. Possible redundancy among the members of the TSC-22/Dip/Bun protein family complicates a genetic analysis. In <it>Drosophila</it>, all proteins homologous to the TSC-22/Dip/Bun family members are derived from a single locus called <it>bunched </it>(<it>bun</it>).</p> <p>Results</p> <p>We have identified <it>bun </it>in an unbiased genetic screen for growth regulators in <it>Drosophila</it>. Rather unexpectedly, <it>bun </it>mutations result in a growth deficit. Under standard conditions, only the long protein isoform BunA – but not the short isoforms BunB and BunC – is essential and affects growth. Whereas reducing <it>bunA </it>function diminishes cell number and cell size, overexpression of the short isoforms BunB and BunC antagonizes <it>bunA </it>function.</p> <p>Conclusion</p> <p>Our findings establish a growth-promoting function of <it>Drosophila </it>BunA. Since the published studies on mammalian systems have largely neglected the long TSC-22 protein version, we hypothesize that the long TSC-22 protein is a functional homolog of BunA in growth regulation, and that it is antagonized by the short TSC-22 protein.</p

Madm (Mlf1 adapter molecule) cooperates with Bunched A to promote growth in Drosophila

Background The TSC-22 domain family (TSC22DF) consists of putative transcription factors harboring a DNA-binding TSC-box and an adjacent leucine zipper at their carboxyl termini. Both short and long TSC22DF isoforms are conserved from flies to humans. Whereas the short isoforms include the tumor suppressor TSC-22 (Transforming growth factor-β1 stimulated clone-22), the long isoforms are largely uncharacterized. In Drosophila, the long isoform Bunched A (BunA) acts as a growth promoter, but how BunA controls growth has remained obscure. Results In order to test for functional conservation among TSC22DF members, we expressed the human TSC22DF proteins in the fly and found that all long isoforms can replace BunA function. Furthermore, we combined a proteomics-based approach with a genetic screen to identify proteins that interact with BunA. Madm (Mlf1 adapter molecule) physically associates with BunA via a conserved motif that is only contained in long TSC22DF proteins. Moreover, Drosophila Madm acts as a growth-promoting gene that displays growth phenotypes strikingly similar to bunA phenotypes. When overexpressed, Madm and BunA synergize to increase organ growth. Conclusions The growth-promoting potential of long TSC22DF proteins is evolutionarily conserved. Furthermore, we provide biochemical and genetic evidence for a growth-regulating complex involving the long TSC22DF protein BunA and the adapter molecule Madm. See minireview at http://jbiol.com/content/9/1/8.ISSN:1478-5854ISSN:1475-492

New indicators and indexes for benchmarking university–industry–government innovation in medical and life science clusters: results from the European FP7 Regions of Knowledge HealthTIES project

Background: While the European Union is striving to become the ‘Innovation Union’, there remains a lack of quantifiable indicators to compare and benchmark regional innovation clusters. To address this issue, a HealthTIES (Healthcare, Technology and Innovation for Economic Success) consortium was funded by the European Union’s Regions of Knowledge initiative, research and innovation funding programme FP7. HealthTIES examined whether the health technology innovation cycle was functioning differently in five European regional innovation clusters and proposed regional and joint actions to improve their performance. The clusters included BioCat (Barcelona, Catalonia, Spain), Medical Delta (Leiden, Rotterdam and Delft, South Holland, Netherlands), Oxford and Thames Valley (United Kingdom), Life Science Zürich (Switzerland), and Innova Észak-Alföld (Debrecen, Hungary). Methods: Appreciation of the ‘triple helix’ of university–industry–government innovation provided the impetus for the development of two quantifiable innovation indexes and related indicators. The HealthTIES H-index is calculated for disease and technology platforms based on the h-index proposed by Hirsch. The HealthTIES Innovation Index is calculated for regions based on 32 relevant quantitative and discriminative indicators grouped into 12 categories and 3 innovation phases, namely ‘Input’ (n = 12), ‘Innovation System’ (n = 9) and ‘Output’ (n = 11). Results: The HealthTIES regions had developed relatively similar disease and technology platform profiles, yet with distinctive strengths and weaknesses. The regional profiles of the innovation cycle in each of the three phases were surprisingly divergent. Comparative assessments based on the indicators and indexes helped identify and share best practice and inform regional and joint action plans to strengthen the competitiveness of the HealthTIES regions. Conclusion: The HealthTIES indicators and indexes provide useful practical tools for the measurement and benchmarking of university–industry–government innovation in European medical and life science clusters. They are validated internally within the HealthTIES consortium and appear to have a degree of external prima facie validity. Potentially, the tools and accompanying analyses can be used beyond the HealthTIES consortium to inform other regional governments, researchers and, possibly, large companies searching for their next location, analyse and benchmark ‘triple helix’ dynamics within their own networks over time, and to develop integrated public–private and cross-regional research and innovation strategies in Europe and beyond