Bunched and Madm Function Downstream of Tuberous Sclerosis Complex to Regulate the Growth of Intestinal Stem Cells in Drosophila.
The Drosophila adult midgut contains intestinal stem cells that support homeostasis and repair. We show here that the leucine zipper protein Bunched and the adaptor protein Madm are novel regulators of intestinal stem cells. MARCM mutant clonal analysis and cell type specific RNAi revealed that Bunched and Madm were required within intestinal stem cells for proliferation. Transgenic expression of a tagged Bunched showed a cytoplasmic localization in midgut precursors, and the addition of a nuclear localization signal to Bunched reduced its function to cooperate with Madm to increase intestinal stem cell proliferation. Furthermore, the elevated cell growth and 4EBP phosphorylation phenotypes induced by loss of Tuberous Sclerosis Complex or overexpression of Rheb were suppressed by the loss of Bunched or Madm. Therefore, while the mammalian homolog of Bunched, TSC-22, is able to regulate transcription and suppress cancer cell proliferation, our data suggest the model that Bunched and Madm functionally interact with the TOR pathway in the cytoplasm to regulate the growth and subsequent division of intestinal stem cells.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Yingchao
Y
Nie
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Qi
Q
Li
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Alla
A
Amcheslavsky
School of Life Sciences, University of Nevada Las Vegas, Las Vegas, NV, 89154, USA.
Juan Carlos
JC
Duhart
Department of Biology, University of Massachusetts Boston, Boston, MA, 02125, USA.
Alexey
A
Veraksa
Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
Hugo
H
Stocker
School of Life Sciences, University of Nevada Las Vegas, Las Vegas, NV, 89154, USA.
Laurel A
LA
Raftery
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA. Tony.Ip@umassmed.edu.
Y Tony
YT
Ip
D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis; D009479:Neuropeptides / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C000608109:Madm protein, Drosophila; D009479:Neuropeptides; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; C490212:Rheb protein, Drosophila; D025521:Tumor Suppressor Proteins; C529273:bun protein, Drosophila; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins
Bunched; Drosophila; Intestine; Madm; Stem cells; TSC-22; Tuberous sclerosis complex