BCL2L12 (Homo sapiens)
- Synonyms: BCL2L12, BCL-2L12
- Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
- Short gene description: Bcl-2-related proline-rich protein (Bcl-2-like 12 protein) [Source:UniProtKB/Swiss-Prot;Acc:Q9HB09]
- Family: Bcl-2 family : multidomain Bcl-2
- Process: apoptosis,
- Pathways: undefined,
- Criteria: manually curated
- Curator comment: It is still debated if Bcl-2L12 has a pro- or antiapoptotic function. Data from Nakajima et al. point towards a slightly pro-apoptotic function that is cell-type specific and so far only shown with UV irradation. On the other hand, the inhibiting function of Bcl-2L12 on caspase-3/-7 downstream of mitochondria cannot be reproduced.
- Mouse ortholog(s): Bcl2l12
- WIKI: BCL2L12-H_sapiens
- Molecular cloning, physical mapping, and expression analysis of a novel gene, BCL2L12, encoding a proline-rich protein with a highly conserved BH2 domain of the Bcl-2 family.
- Scorilas A, Kyriakopoulou L, Yousef GM, Ashworth LK, Kwamie A, Diamandis EP
- Members of the Bcl-2 family of apoptosis-regulating proteins contain at least one of the four evolutionarily conserved domains, termed BH1, BH2, BH3, or BH4. Here, we report the identification, cloning, physical mapping, and expression pattern of BCL2L12, a novel gene that encodes a BCL2-like proline-rich protein. Proline-rich sites have been shown to interact with Src homology region 3 (SH3) domains of several tyrosine kinases, mediating their oncogenic potential. This new gene maps to chromosome 19q13.3 and is located between the IRF3 and the PRMT1/HRMT1L2 genes, close to the RRAS gene. BCL2L12 is composed of seven coding exons and six intervening introns, spanning a genomic area of 8.8 kb. All of the exon-intron splice sites conform to the consensus sequence for eukaryotic splice sites. The BCL2L12 protein is composed of 334 amino acids, with a calculated molecular mass of 36.8 kDa and an isoelectric point of 9.45. The BCL2L12 protein contains one BH2 homology domain, one proline-rich region similar to the TC21 protein and, five consensus PXXP tetrapeptide sequences. BCL2L12 is expressed mainly in breast, thymus, prostate, fetal liver, colon, placenta, pancreas, small intestine, spinal cord, kidney, and bone marrow and to a lesser extent in many other tissues. We also identified one splice variant of BCL2L12 that is primarily expressed in skeletal muscle. Genomics. 2001 Mar 1;72(2):217-21.
- Cell type-dependent proapoptotic role of Bcl2L12 revealed by a mutation concomitant with the disruption of the juxtaposed Irf3 gene.
- Nakajima A, Nishimura K, Nakaima Y, Oh T, Noguchi S, Taniguchi T, Tamura T
- The generation of mice lacking the expression of the IRF3 transcription factor (Irf3(-/-) mice) has revealed its crucial role in the activation of the type I IFN response. The Bcl2l12 gene, encoding Bcl2L12 protein structurally related to the Bcl-2 family, was found to almost overlap with the Irf3 gene, and the null mutation previously introduced into the Irf3 allele resulted in the functional inactivation of the Bcl2l12 gene; therefore, the mice are correctly termed Irf3(-/-)Bcl2l12(-/-) mice. Embryonic fibroblasts from Irf3(-/-)Bcl2l12(-/-) mice (Irf3(-/-)Bcl2l12(-/-) MEFs) showed resistance to DNA damage-induced apoptosis, accompanied by impaired caspase cleavage. This apoptotic defect in Irf3(-/-)Bcl2l12(-/-) MEFs was rescued by the ectopic expression of Bcl2L12, but not IRF3. The Bcl2L12-mediated apoptotic response depended on the cell type and extracellular stimulus. In contrast, the previously reported defect in the induction of type I IFN genes by nucleic acids in Irf3(-/-)Bcl2l12(-/-) MEFs was rescued by expressing IRF3, but not Bcl2L12. Thus, our present study revealed, on the one hand, a cell type-dependent proapoptotic function of Bcl2L12 and, on the other hand, confirmed the essential role of IRF3 in type I IFN response. Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12448-52. Epub 2009 Jul 17.
- Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma.
- Stegh AH,Kim H,Bachoo RM,Forloney KL,Zhang J,Schulze H,Park K,Hannon GJ,Yuan J,Louis DN,DePinho RA,Chin L
- Glioblastoma (GBM) is an astrocytic brain tumor characterized by an aggressive clinical course and intense resistance to all therapeutic modalities. Here, we report the identification and functional characterization of Bcl2L12 (Bcl2-like-12) that is robustly expressed in nearly all human primary GBMs examined. Enforced Bcl2L12 expression confers marked apoptosis resistance in primary cortical astrocytes, and, conversely, its RNA interference (RNAi)-mediated knockdown sensitizes human glioma cell lines toward apoptosis in vitro and impairs tumor growth with increased intratumoral apoptosis in vivo. Mechanistically, Bcl2L12 expression does not affect cytochrome c release or apoptosome-driven caspase-9 activation, but instead inhibits post-mitochondrial apoptosis signaling at the level of effector caspase activation. One of Bcl2L12s mechanisms of action stems from its ability to interact with and neutralize caspase-7. Notably, while enforced Bcl2L12 expression inhibits apoptosis, it also engenders a pronecrotic state, which mirrors the cellular phenotype elicited by genetic or pharmacologic inhibition of post-mitochondrial apoptosis molecules. Thus, Bcl2L12 contributes to the classical tumor biological features of GBM such as intense apoptosis resistance and florid necrosis, and may provide a target for enhanced therapeutic responsiveness of this lethal cancer. Genes Dev. 2007 Jan 1;21(1):98-111.
- Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma.
- Stegh AH,Kesari S,Mahoney JE,Jenq HT,Forloney KL,Protopopov A,Louis DN,Chin L,DePinho RA
- Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that is characterized by the paradoxical features of intense apoptosis resistance yet a marked propensity to undergo necrosis. Bcl2L12 (for Bcl2-Like12) is a nuclear and cytoplasmic oncoprotein that is universally overexpressed in primary GBM and functions to block postmitochondrial apoptosis signaling by neutralizing effector caspase-3 and caspase-7 maturation. This postmitochondrial block in apoptosis engenders the alternate cell fate of cellular necrosis, thus providing a molecular explanation for GBMs classical features. Whereas Bcl2L12-mediated neutralization of caspase-7 maturation involves physical interaction, the mechanism governing Bcl2L12-mediated inhibition of caspase-3 activity is not known. The nuclear localization of Bcl2L12 prompted expression profile studies of primary astrocytes engineered to overexpress Bcl2L12. The Bcl2L12 transcriptome revealed a striking induction of the small heat shock protein alpha-basic-crystallin (alphaB-crystallin/HspB5), a link reinforced by robust alphaB-crystallin expression in Bcl2L12-expressing orthotopic glioma and strong coexpression of alphaB-crystallin and Bcl2L12 proteins in human primary GBMs. On the functional level, enforced alphaB-crystallin or Bcl2L12 expression enhances orthotopic tumor growth. Conversely, RNAi-mediated knockdown of alphaB-crystallin in Bcl2L12-expressing astrocytes and glioma cell lines with high endogenous alphaB-crystallin showed enhanced apoptosis, yet decreased necrotic cell death with associated increased caspase-3 but not caspase-7 activation. Mirroring this specific effect on effector caspase-3 activation, alphaB-crystallin selectively binds pro-caspase-3 and its cleavage intermediates in vitro and in vivo. Thus, alphaB-crystallin is a Bcl2L12-induced oncoprotein that enables Bcl2L12 to block the activation of both effector caspases via distinct mechanisms, thereby contributing to GBM pathogenesis and its hallmark biological properties. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10703-8. Epub 2008 Jul 31.
Structure & Sequence [+]
Protein sequence [+]
BCL2L12 | Homo sapiens | 9606 | length:334
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Homologs list [+]
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Gene Ontology [+]
Information from other databases [+]
- OMIM gene information: 610837
- OMIM disease information:
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