harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-XL

We report the identification, cloning and characterization of harakiri, a novel gene that regulates apoptosis

N. Inohara

2002

Scholarcy highlights

  • Apoptosis, a morphologically distinguished form of programmed cell death, is critical during development and tissue homeostasis and in the pathogenesis of a variety of diseases including cancer, autoimmune disease, viral infection and neurodegenerative disorders
  • The precise mechanisms that regulate apoptosis have not been elucidated; it appears that this form of cell death is controlled by a genetic program which is activated in the dying cell
  • Two-hybrid screening for proteins that bind to Bcl-2 reveals a novel protein that interacts with anti-apoptosis proteins Bcl-2 and Bcl-XL but not with death-promoting proteins Bax and Bak To search for Bcl-2-interacting proteins, we screened a HeLa cDNA library using GAL4–Bcl-2 as a ‘bait’ in the yeast two-hybrid assay
  • Hrk interacts with Bcl-2 and Bcl-XL in mammalian cells To confirm that Hrk associates with Bcl-2 and Bcl-XL in mammalian cells, a 293T human kidney cell line was transiently co-transfected with expression plasmids producing a Flag-tagged Hrk protein and Bcl-2, Bcl-XL or harakiri activates apoptosis control plasmid
  • A novel regulator of apoptosis that exhibits death-inducing activity in mammalian cells
  • The BH3 region appears to represent a critical domain for interaction with Bcl-2 family members and regulation of apoptosis
  • It is possible that there are subtle differences in the function of Hrk and Bik/Nbk. In this respect, it has been shown that Bcl-XS interacts with Bik/Nbk, but our analysis revealed that Bcl-XS fails to associate with Hrk. In addition, Hrk and Bik/Nbk differ in their pattern of expression in tissues, which suggests that they play distinct roles in the regulation of apoptosis in vivo

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