Oncogene database

598

BCL2L1

BCL2-like 1;BCL2L1;BCL2-like 1

apoptosis regulator Bcl-X|bcl-2-like protein 1|protein phosphatase 1, regulatory subunit 52

20q11.21

protein-coding

The discovery two decades ago that the Philadelphia chromosome encodes an oncogenic fusion of Bcr and Abl remains among the most important contributions to our understanding of the process of malignant transformation. We now know that Bcr-Abl is one of more than 30 aberrantly activated tyrosine kinases that are expressed in a variety of tumors. Conventional treatment of the tumors in which these proteins are expressed is usually doomed to failure because the activated tyrosine kinases render the tumor cells stubbornly resistant to apoptosis. In this context, it is notable that Zhao and coworkers have uncovered a novel weapon in the resistance armamentarium of these rogue kinases, the suppression of the inactivating deamidation of Bcl-xL (this issue of cancer Cell).

Murine coronavirus mouse hepatitis virus (MHV) causes persistent infection of the central nervous system (CNS) in rodents, which has been associated with demyelination. However, the precise mechanism of MHV persistence in the CNS remains elusive. Here we show that the progenitor oligodendrocytes (central glial 4 [CG-4] cells) derived from newborn rat brain were permissive to MHV infection, which resulted in cell death, although viral replication was restricted. Interestingly, treatment with fetal bovine serum or exogenous expression of cellular oncogene Bcl-xL prevented CG-4 cells from MHV-induced cell death. Significantly, overexpression of Bcl-xL alone was sufficient to convert acute to persistent, nonproductive infection in CG-4 cells. This finding indicates that intracellular factors rather than viral components play a critical role in establishing viral persistence in CNS cells. Although viral genomic RNAs continuously persisted in Bcl-xL-expressing CG-4 cells over 10 passages, infectious virus could no longer be isolated beyond 2 passages of the cell. Such a phenomenon resembles the persistent MHV infection in animal CNS. Thus, the establishment of a persistent, nonproductive infection in CG-4 cells may provide a useful in vitro model for studying viral persistence in animal CNS. The data also suggest that direct virus-host cell interaction is one of the underlying mechanisms that regulate viral persistence in CNS cells.

The rate of apoptosis varies in malignant tumors, and it can be involved in diminishing tumor size. Different protein-regulators of apoptosis, such as Bcl-2, BclX, and Bax have an influence on the rate of apoptosis in various tumors. In human renal diseases, such as the experimental model of acute renal failure, and many tumors, including Wilms tumor, the expression of antiapoptotic members of Bcl-2 family is increased, while the expression of proapoptotic members is low. AIM: The aim of our study was to investigate Bcl-X(S/L) protein expression in Wilms tumor, to compare it with the expression in normal renal tissue, as well as to see if there is a correlation between Bcl-X(S/L) expression in Wilms tumor with tumor stage, histological type, prognostic group, or response to preoperative chemotherapy. MATERIALS AND METHODS: Twenty-eight cases of Wilms tumor (two cases with metastasis) and two samples of normal kidney tissue were studied using streptavidin-biotin-complex technique. Bcl-X(S/L) expression levels were semiquantitatively scored. RESULTS: The expression of Bcl-X(S/L) was observed in the majority of cases (60.7%), more often in the blastemal than in the epithelial component of Wilms tumor: 60.7% and 28.6%, respectively (p=0.02). There was a statistically significant inverse relationship between Bcl-X(S/L) expression and tumor stage (p=0.015). Bcl-X(S/L) was found less frequently in high-risk tumors then in tumors with good prognosis (p=0.02). Treated Wilms tumors showed Bcl-X(S/L) expression more often than nontreated tumors, but the relationship was not statistically significant (p=0.08). expression of Bcl-X(S/L) was detected in various histological types of Wilms tumor, but there was no statistically significant association (p=0.82) except in cases with diffuse anaplasia (p=0.012), which were always negative. No Bcl-X(S/L) immunostaining was observed in two cases of metastasis or in one case of bilateral Wilms tumor. CONCLUSION: Our results suggest that the expression of Bcl-X(S/L) protein is associated with prognostic group, tumor stage, and presence of anaplasia.

The nature of the bcl-2 family of proto-oncogenes was analyzed by sequence alignment, secondary structure prediction, and phylogenetic techniques. Phylogenies were inferred from both the nucleic acid and amino acid sequences of the human, murine, rat, and chicken sequences for BCL-2 and BCL-X, human MCL1, murine A1, the nematode Caenorhabditis elegans and Caenorhabditis briggsiae ced-9 proteins, and the sequences BHRF1 from Epstein-Barr and LMW5-HL from African swine fever viruses. Both sequence alignment and secondary structure prediction techniques supported the conservation of both the overall secondary structure and the carboxy-terminal transmembrane domain in ALL members of the family. ALL the treeing methods employed (distance matrix, maximum likelihood, and parsimony) supported a tree in which the proapoptotic proteins BCL-2 and BCL-X represent the most recent additions to the group. ALL the trees also indicated that the viral proteins BHRF1 and LMW-HL arose from a common ancestor, an ancestor they shared in common with the pro-apoptotic control protein BAX, indicating that this function of BAX evolved only recently. The most ancient branches are represented by the nematode ced-9 protein and by the control genes MCL1 and A1, which in the treeing methods employed represent separate lineages within the most ancient grouping. These results demonstrate the evolution of a highly conserved family of developmental control genes from nematode to man--genes that encode proteins essential for normal development but which are highly conserved in terms of predicted structure and possible cellular localization. The evolutionary analysis also indicates that the family may be even larger than originally predicted and that other members are waiting to be discovered.