BCL2A1

BCL2A1 Background

Bcl-2-related protein A1 also called Bcl-2 related gene expressed in fetal liver (Bfl-1), is a protein in humans that is encoded by the BCL2A1 gene on chromosome 15q24.3 ^[1]. BCL2A1 possesses four BH-domain: BH1-BH4. Crystal structures of BCL2A1 in complex with BH3-peptides revealed that it displays a similar hydrophobic groove as observed on all related anti-apoptotic Bcl-2 (B-cell lymphoma 2) proteins ^[2]. Although BCL2A1 does not exhibit a well-defined C-terminal transmembrane domain identified in other anti-apoptotic Bcl-2 proteins, its C-terminus is essential for the anti-apoptotic function and the subcellular localization of BCL2A1 ^[3]. BCL2A1 protein is particularly important in the hematopoietic system ^[10] and executes its anti-apoptotic function by sequestering pro-apoptotic BCL2 proteins ^[4]. The transcription of BCL2A1 is induced by NF-kappa B^[5], retinoic X receptors (RXR) agonists ^[6], and WT-1 ^[7], but inhibited by the plasma cell transcription factor PRDI-BF1/Blimp-1 ^[8]. The identification of BCL2A1 as an NF-κB target gene shows that the formation of inflammasomes may also induce the expression of BCL2A1, thus promoting the survival of the pro-inflammatory cells during inflammation. The stability of BCL2A1 protein is regulated by proteasomal degradation ^[9]. BCL2A1 overexpression has been found in various hematological malignancies ^[10] as well as solid tumors ^[11] and seems to be notably associated with advanced or metastatic disease stages ^[12]. Besides a potential role in tumorigenesis, BCL2A1 overexpression is also involved in the resistance for chemotherapy.

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[2] Herman MD, Nyman T, et al. Completing the family portrait of the anti-apoptotic Bcl-2 proteins: crystal structure of human Bfl-1 in complex with Bim & FEBS Lett 2008; 582: 3590-3594.
[3] Brien G, Debaud AL, et al. C-terminal residues regulate localization and function of the antiapoptotic protein Bfl-1 [J]. J Biol Chem 2009; 284: 30257-30263.
[4] M Vogler. BCL2A1: the underdog in the BCL2 family [J]. Cell Death & Differentiation volume 19, 2012, pages67-74.
[5] Zong WX, Edelstein et al. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis [J]. Genes Dev 1999; 13: 382-387.
[6] Rasooly R, Schuster GU, et al. Retinoid x receptor agonists increase bcl2a1 expression and decrease apoptosis of naive T lymphocytes [J]. J Immunol 2005; 175: 7916-7929.
[7] Simpson LA, Burwell EA, et al. The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy. [J]. Blood 2006; 107: 4695-4702.
[8] Shaffer AL, Lin KI, et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. [J]. Immunity 2002; 17: 51-62.
[9] Herold MJ, Zeitz J, et al. The stability and anti-apoptotic function of A1 are controlled by its C terminus [J]. J Biol Chem 2006; 281: 13663-13671.
[10] Choi SS, Park IC, et al. A novel Bcl-2 related gene, Bfl-1, is overexpressed in stomach cancer and preferentially expressed in bone marrow [J]. Oncogene 1995; 11: 1693-1698.
[11] Park IC, Lee SH, et al. Expression of a novel Bcl-2 related gene, Bfl-1, in various human cancers and cancer cell lines [J]. Anticancer Res 1997; 17: 4619-4622.
[12] Yoon HS, Hong SH, et al. Bfl-1 gene expression in breast cancer: its relationship with other prognostic factors [J]. J Korean Med Sci 2003; 18: 225-230.