Essential role for Bclaf1 in lung development and immune system function

Abstract

Bcl-2 associated factor 1 (Bclaf1) is a nuclear protein that was originally identified in a screen of proteins that interact with the adenoviral bcl-2 homolog E1B19K. Overexpression of Bclaf1 was shown to result in apoptosis and transcriptional repression that was reversible in the presence of Bcl-2 or Bcl-x L . Furthermore, antiapoptotic members, but not proapoptotic members of the Bcl-2 protein family, were shown to interact with Bclaf1 and prevent its localization to the nucleus. Bclaf1 has also recently been identified as a binding partner for Emerin, a nuclear membrane protein that is mutated in X-linked recessive Emery-Dreifuss muscular dystrophy. To ascertain the in vivo function of Bclaf1, we have generated mice that carry a targeted mutation of the bclaf1 locus. In this study, we show that Bclaf1 is required for proper spatial and temporal organization of smooth muscle lineage during the saccular stage of lung development. We also show that Bclaf1 is dispensable for thymocyte development but is essential for peripheral T-cell homeostasis. Despite its postulated role as a proapoptotic protein, Bclaf1-deficient cells did not show any defect in cell death linked to development or after exposure to various apoptotic stimuli. Our findings show a critical role for Bclaf1 in developmental processes independent of apoptosis. Cell Death and Differentiation (2009) Apoptosis is a critical component of normal development and the cellular response to radio-and chemotherapy. 1,2 Two distinct apoptotic pathways have been characterized: the extrinsic pathway triggered by transmembrane death receptors and the intrinsic pathway that signals through mitochondria. Members of the Bcl-2 protein family primarily impact the intrinsic pathway by controlling mitochondrial membrane permeability, the release of proapoptotic mitochondrial proteins, and caspase activation. 1 Proapoptotic Bcl-2 proteins such as Bak and Bax are activated directly after interactions with the 'BH3-only' Bcl-2 protein Bid. In addition, binding of other BH3-only proteins such as Noxa, Puma, Bad, and Bim to antiapoptotic Bcl-2 proteins (Bcl-2 or Bcl-x L ) results in activation of Bax and Bak. [3][4][5] Bcl-2 associated factor 1 (Bclaf1; also known as Bcl-2-associated transcription factor or Btf) was originally identified in a screen for adenoviral E1B19K protein partners. 6 Subsequent studies with Bclaf1 S , an alternatively-spliced form missing amino acid residues 797-846, showed interactions with Bcl-2 and Bcl-x L . E1B19K, Bcl-2, and Bcl-x L were found to sequester Bclaf1 S to the nuclear periphery and cytoplasm. Ectopic Bclaf1 induced apoptosis as well as transcriptional repression, properties that were reversed in the presence of antiapoptotic Bcl-2 members. 6 Although these findings implicate Bclaf1 in apoptotic signaling, Bclaf1 does not show structural similarities to Bcl-2 family members. Bclaf1 contains an N-terminal tract of Arg-Ser repeats (RS domain) that is typical of pre-mRNA processing factors and was identified in interchromatin granule c...

BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

“…Forced expression of BCLAF1 can induce apoptosis in HeLa cells 1 , suggesting a role for BCLAF1 in apoptotic signalling. However, the role in apoptotic pathway remains controversial, as cells from BCLAF1-deficient mice do not have obvious defects in apoptosis 2 . Indeed, multiple functions have been described for BCLAF1 by different groups, such as in posttranscriptional processes 3,4 , production of Kaposi's sarcoma-associated herpesvirus 5 and human cytomegalovirus infection 6 , lung development and T-cell activation 2,7 .…”

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

“…19 Bclaf1 knockout mice are embryonic lethal because of defects in lung development. 20 Ectopical Bclaf1 expression induces apoptosis in various cell types or autophagic cell death in myeloma cells. 19,21 However, thymocytes and splenocytes isolated from Bclaf1 knockout mice exhibit normal responsiveness to various apoptotic stimulations, thus arguing its role in apoptosis at physiological levels.…”

“…19,21 However, thymocytes and splenocytes isolated from Bclaf1 knockout mice exhibit normal responsiveness to various apoptotic stimulations, thus arguing its role in apoptosis at physiological levels. 20 The Bclaf1 protein contains homologies to the basic zipper (bZIP) and Myb DNA-binding domain and can bind to DNA. 19 Several studies suggested a role of Bclaf1 in DDR.…”

BCLAF1 (BCL2-associated transcription factor 1)

“…BCLAF1 is ubiquitously expressed, with high steadystate mRNA levels in skeletal muscle, haematopoietic cells, and various other cell lineages (Kasof et al, 1999;McPherson et al, 2009). Steadystate levels of BCLAF1 protein fluctuate in a temporal and cell-lineage dependent fashion during development (McPherson et al, 2009).…”

“…Steadystate levels of BCLAF1 protein fluctuate in a temporal and cell-lineage dependent fashion during development (McPherson et al, 2009). …”