Menin Is a Regulator of the Stress Response in Drosophila melanogaster

Abstract

Menin, the product of the multiple endocrine neoplasia type I gene, has been implicated in several biological processes, including the control of gene expression and apoptosis, the modulation of mitogen-activated protein kinase pathways, and DNA damage sensing or repair. In this study, we have investigated the function of menin in the model organism Drosophila melanogaster. We show that Drosophila lines overexpressing menin or an RNA interference for this gene develop normally but are impaired in their response to several stresses, including heat shock, hypoxia, hyperosmolarity and oxidative stress. In the embryo subjected to heat shock, this impairment was characterized by a high degree of developmental arrest and lethality. The overexpression of menin enhanced the expression of HSP70 in embryos and interfered with its down-regulation during recovery at the normal temperature. In contrast, the inhibition of menin with RNA interference reduced the induction of HSP70 and blocked the activation of HSP23 upon heat shock, Menin was recruited to the Hsp70 promoter upon heat shock and menin overexpression stimulated the activity of this promoter in embryos. A 70-kDa inducible form of menin was expressed in response to heat shock, indicating that menin is also regulated in conditions of stress. The induction of HSP70 and HSP23 was markedly reduced or absent in mutant embryos harboring a deletion of the menin gene. These embryos, which did not express the heat shock-inducible form of menin, were also hypersensitive to various conditions of stress. These results suggest a novel role for menin in the control of the stress response and in processes associated with the maintenance of protein integrity.

ACKNOWLEDGMENTS

We thank John Lis and Susan Lindquist for providing the Hsp70-lacZ strain and HSP70 antibody, respectively. Sunita Agarwal kindly provided the cDNA for human menin. We gratefully acknowledge Tim Westwood for the heat shock factor antiserum and invaluable advice provided throughout this investigation. We are indebted to Colin Nurse for advice on the hypoxia experiments. We thank Xiao Li Zhao and Guangyian Zhao for their excellent technical work and Randy Elkasabgy and Dorothy DeSousa for their support and technical advice. We are also grateful to Michelle Benderly, who was involved in the early stages of this project. Several strains employed in this study were obtained from the Bloomington Stock Center.

This work was made possible by grants from the Collaborative Health Research Program of the Natural Sciences and Engineering Research Council of Canada (grant 237997-2000) and the National Cancer Institute of Canada (NCIC grant 15201) to A.R.C. and P.-A.B. and from the Canadian Institutes of Health Research to R.M.T. (grant MOP-43958) and P.-A.B. (grant MOP-10272).