Proapoptotic BH3-Only Bcl-2 Family Member Bik/Blk/Nbk Is Expressed in Hemopoietic and Endothelial Cells but Is Redundant for Their Programmed Death

Abstract

The BH3-only members of the Bcl-2 protein family are essential for initiation of programmed cell death and stress-induced apoptosis. We have determined the expression pattern in mice of the BH3-only protein Bik, also called Blk or Nbk, and examined its physiological function by gene targeting. We found that Bik is expressed widely in the hematopoietic compartment and in endothelial cells of the venous but not arterial lineages. Nevertheless, its loss did not increase the numbers of such cells in mice or protect hematopoietic cells in vitro from apoptosis induced by cytokine withdrawal or diverse other cytotoxic stimuli. Moreover, whereas loss of the BH3-only protein Bim rescued mice lacking the prosurvival protein Bcl-2 from fatal polycystic kidney disease and lymphopenia, loss of Bik did not. These results indicate that any function of Bik in programmed cell death and stress-induced apoptosis must overlap that of other BH3-only proteins.

We thank Kim Newton (Genentech, Inc., South San Francisco, Calif.) for providing cDNA templates for expression analysis; M. Cancilla (Exelixis, Inc., South San Francisco, Calif.) and L. Tai for assistance with BAC manipulation and blk locus mapping; A. Steptoe for ES cell manipulation; F. Battye, C. Tarlinton, V. Lapatis, and C. Clark for cell sorting; A. Naughton, C. Tilbrook, J. Morrow, N. Clark, and K. Birchall for animal husbandry and care; S. Mihajlovic and E. Tsui for histology; and S. Cory, D. Huang, A. Harris, D. Vaux, H. Puthalakath, and L. O'Reilly for insightful discussions.

This work was supported by fellowships and grants from the NHMRC (Canberra), the Dr Josef Steiner Cancer Research Foundation (Bern), the Leukemia and Lymphoma Society, and the NIH (CA80188). L.C. is a recipient of The Cancer Council Victoria Postdoctoral Cancer Research Fellowship.