title: Interaction of delta-like 1 homolog (Drosophila) with prohibitins and its impact on tumor cell clonogenicity.
abstract: Cancer stem cell characteristics, especially their self-renewal and clonogenic potentials, play an essential role in malignant progression and response to anticancer therapies. Currently, it remains largely unknown what pathways are involved in the regulation of cancer cell stemness and differentiation. Previously, we found that delta-like 1 homolog (Drosophila) or DLK1, a developmentally regulated gene, plays a critical role in the regulation of differentiation, self-renewal, and tumorigenic growth of neuroblastoma cells. Here, we show that DLK1 specifically interacts with the prohibitin 1 (PHB1) and PHB2, two closely related genes with pleiotropic functions, including regulation of mitochondrial function and gene transcription. DLK1 interacts with the PHB1-PHB2 complex via its cytoplasmic domain and regulates mitochondrial functions, including mitochondrial membrane potential and production of reactive oxygen species. We have further found that PHB1 and especially PHB2 regulate cancer cell self-renewal as well as their clonogenic potential. Hence, the DLK1-PHB interaction constitutes a new signaling pathway that maintains clonogenicity and self-renewal potential of cancer cells.
  
  
  CONCLUSIONS
  This study provides a new mechanistic insight into the regulation of the stem cell characteristics of cancer cells.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT 06520-8040. zhong.yun@yale.edu.
authors.forename: Asma
authors.initials: A
authors.lastname: Begum
authors.forename: Qun
authors.initials: Q
authors.lastname: Lin
authors.forename: Chenye
authors.initials: C
authors.lastname: Yu
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kim
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yun
mesh_terms: D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology*; D000091402:Prohibitins; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000717328:PHB protein, human; C000717331:PHB2 protein, human; D000091402:Prohibitins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012097:Repressor Proteins