Functional Cooperation of the Proapoptotic Bcl2 Family Proteins Bmf and Bim in Vivo

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2009 Oct 21

PMID 19841067

Citations 43

Authors

Anette Hubner

Julie Cavanagh-Kyros

Mercedes Rincon

Richard A Flavell

Roger J Davis

Affiliations

Soon will be listed here.

Abstract

Bcl2-modifying factor (Bmf) is a member of the BH3-only group of proapoptotic proteins. To test the role of Bmf in vivo, we constructed mice with a series of mutated Bmf alleles that disrupt Bmf expression, prevent Bmf phosphorylation by the c-Jun NH(2)-terminal kinase (JNK) on Ser(74), or mimic Bmf phosphorylation on Ser(74). We report that the loss of Bmf causes defects in uterovaginal development, including an imperforate vagina and hydrometrocolpos. We also show that the phosphorylation of Bmf on Ser(74) can contribute to a moderate increase in levels of Bmf activity. Studies of compound mutants with the related gene Bim demonstrated that Bim and Bmf exhibit partially redundant functions in vivo. Thus, developmental ablation of interdigital webbing on mouse paws and normal lymphocyte homeostasis require the cooperative activity of Bim and Bmf.

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References

Rodriguez I, Araki K, Khatib K, Martinou J, Vassalli P . Mouse vaginal opening is an apoptosis-dependent process which can be prevented by the overexpression of Bcl2. Dev Biol. 1997; 184(1):115-21. DOI: 10.1006/dbio.1997.8522. View

Hutcheson J, Scatizzi J, Bickel E, Brown N, Bouillet P, Strasser A . Combined loss of proapoptotic genes Bak or Bax with Bim synergizes to cause defects in hematopoiesis and in thymocyte apoptosis. J Exp Med. 2005; 201(12):1949-60. PMC: 2212027. DOI: 10.1084/jem.20041484. View

Gavathiotis E, Suzuki M, Davis M, Pitter K, Bird G, Katz S . BAX activation is initiated at a novel interaction site. Nature. 2008; 455(7216):1076-81. PMC: 2597110. DOI: 10.1038/nature07396. View

Willis S, Fletcher J, Kaufmann T, van Delft M, Chen L, Czabotar P . Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science. 2007; 315(5813):856-9. DOI: 10.1126/science.1133289. View

Hubner A, Barrett T, Flavell R, Davis R . Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol Cell. 2008; 30(4):415-25. PMC: 2453504. DOI: 10.1016/j.molcel.2008.03.025. View

LINDSTEN T, Ross A, King A, Zong W, Rathmell J, Shiels H . The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell. 2001; 6(6):1389-99. PMC: 3057227. DOI: 10.1016/s1097-2765(00)00136-2. View

Yoshida H, Kong Y, Yoshida R, Elia A, Hakem A, Hakem R . Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell. 1998; 94(6):739-50. DOI: 10.1016/s0092-8674(00)81733-x. View

Puthalakath H, Huang D, OReilly L, King S, Strasser A . The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell. 1999; 3(3):287-96. DOI: 10.1016/s1097-2765(00)80456-6. View

Cecconi F, Meyer B, Roth K, Gruss P . Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell. 1998; 94(6):727-37. DOI: 10.1016/s0092-8674(00)81732-8. View

10.

Honarpour N, Du C, Richardson J, Hammer R, Wang X, Herz J . Adult Apaf-1-deficient mice exhibit male infertility. Dev Biol. 2000; 218(2):248-58. DOI: 10.1006/dbio.1999.9585. View

11.

Zhang Y, Adachi M, Kawamura R, Imai K . Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ. 2005; 13(1):129-40. DOI: 10.1038/sj.cdd.4401686. View

12.

Show M, Hill C, Anway M, Wright W, Zirkin B . Phosphorylation of mitogen-activated protein kinase 8 (MAPK8) is associated with germ cell apoptosis and redistribution of the Bcl2-modifying factor (BMF). J Androl. 2008; 29(3):338-44. DOI: 10.2164/jandrol.107.003558. View

13.

Weston C, Davis R . The JNK signal transduction pathway. Curr Opin Cell Biol. 2007; 19(2):142-9. DOI: 10.1016/j.ceb.2007.02.001. View

14.

VanBrocklin M, Verhaegen M, Soengas M, Holmen S . Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res. 2009; 69(5):1985-94. PMC: 2665192. DOI: 10.1158/0008-5472.CAN-08-3934. View

15.

Kepp O, Gottschalk K, Churin Y, Rajalingam K, Brinkmann V, Machuy N . Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection. PLoS Pathog. 2009; 5(3):e1000348. PMC: 2654407. DOI: 10.1371/journal.ppat.1000348. View

16.

Kuida K, Haydar T, Kuan C, Gu Y, Taya C, Karasuyama H . Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell. 1998; 94(3):325-37. DOI: 10.1016/s0092-8674(00)81476-2. View

17.

Bouillet P, Metcalf D, Huang D, Tarlinton D, Kay T, Kontgen F . Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science. 1999; 286(5445):1735-8. DOI: 10.1126/science.286.5445.1735. View

18.

Farley N, Pedraza-Alva G, Serrano-Gomez D, Nagaleekar V, Aronshtam A, Krahl T . p38 mitogen-activated protein kinase mediates the Fas-induced mitochondrial death pathway in CD8+ T cells. Mol Cell Biol. 2006; 26(6):2118-29. PMC: 1430304. DOI: 10.1128/MCB.26.6.2118-2129.2006. View

19.

Morales A, Gutman D, Lee K, Boise L . BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide-induced cell death in myeloma. Blood. 2008; 111(10):5152-62. PMC: 2384139. DOI: 10.1182/blood-2007-10-116889. View

20.

Schmelzle T, Mailleux A, Overholtzer M, Carroll J, Solimini N, Lightcap E . Functional role and oncogene-regulated expression of the BH3-only factor Bmf in mammary epithelial anoikis and morphogenesis. Proc Natl Acad Sci U S A. 2007; 104(10):3787-92. PMC: 1820662. DOI: 10.1073/pnas.0700115104. View