Organotypic Brain Slice Culture Microglia Exhibit Molecular Similarity to Acutely-Isolated Adult Microglia and Provide a Platform to Study Neuroinflammation.

Microglia are central nervous system (CNS) resident immune cells that have been implicated in neuroinflammatory pathogenesis of a variety of neurological conditions. Their manifold context-dependent contributions to neuroinflammation are only beginning to be elucidated, which can be attributed in part to the challenges of studying microglia and the lack of tractable systems to study microglia function. Organotypic brain slice cultures offer a tissue-relevant context that enables the study of CNS resident cells and the analysis of brain slice microglial phenotypes has provided important insights, in particular into neuroprotective functions.

Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects.

Neural tube defects (NTDs) are common birth defects in humans and show an unexplained female bias. Female mice lacking the tumor suppressor p53 display NTDs with incomplete penetrance. We found that the combined loss of pro-apoptotic BIM and p53 caused 100% penetrant, female-exclusive NTDs, which allowed us to investigate the female-specific functions of p53.

Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK.

Intrinsic apoptosis, reliant on BAX and BAK, has been postulated to be fundamental for morphogenesis, but its precise contribution to this process has not been fully explored in mammals. Our structural analysis of BOK suggests close resemblance to BAX and BAK structures. Notably, BokBaxBak animals exhibited more severe defects and died earlier than BaxBak mice, implying that BOK has overlapping roles with BAX and BAK during developmental cell death.

RAG-induced DNA lesions activate proapoptotic BIM to suppress lymphomagenesis in p53-deficient mice.

Neoplastic transformation is driven by oncogenic lesions that facilitate unrestrained cell expansion and resistance to antiproliferative signals. These oncogenic DNA lesions, acquired through errors in DNA replication, gene recombination, or extrinsically imposed damage, are thought to activate multiple tumor suppressive pathways, particularly apoptotic cell death. DNA damage induces apoptosis through well-described p53-mediated induction of PUMA and NOXA.

Loss of PUMA (BBC3) does not prevent thrombocytopenia caused by the loss of BCL-XL (BCL2L1).

Apoptosis is required to maintain tissue homeostasis in multicellular organisms. Platelets, the anucleate cells that are essential for blood clotting, are a prime example. Their brief life span in the circulation is regulated by the intrinsic apoptosis pathway.

Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis.

MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven-lymphoma development owing to a reduction in lymphoma initiating pre-B cells.

Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies.

The 'hallmarks of cancer' are generally accepted as a set of genetic and epigenetic alterations that a normal cell must accrue to transform into a fully malignant cancer. It follows that therapies designed to counter these alterations might be effective as anti-cancer strategies. Over the past 30 years, research on the BCL-2-regulated apoptotic pathway has led to the development of small-molecule compounds, known as 'BH3-mimetics', that bind to pro-survival BCL-2 proteins to directly activate apoptosis of malignant cells.

Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress.

Understanding the critical factors that govern recovery of the hematopoietic system from stress, such as during anticancer therapy and bone marrow transplantation, is of clinical significance. We investigated the importance of the prosurvival proteins myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma-extra large (BCL-XL) in stem/progenitor cell survival and fitness during hematopoietic recovery from stress. Loss of a single Mcl-1 allele, which reduced MCL-1 protein levels, severely compromised hematopoietic recovery from myeloablative challenge and following bone marrow transplantation, whereas BCL-XL was dispensable in both contexts.

MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice.

Apoptosis plays a role in normal lymphopoiesis and lymphoid malignancies. Pro-survival MCL-1 is essential for survival of T-cell progenitors, BCL-XL for immature thymocytes, and BCL-2 for mature T cells. Conversely, little is known about the regulators that are required for the survival of T-cell lymphomas.

The role of the apoptotic machinery in tumor suppression.

Multicellular organisms have evolved processes to prevent abnormal proliferation or inappropriate tissue infiltration of cells, and these tumor suppressive mechanisms serve to prevent tissue hyperplasia, tumor development, and metastatic spread of tumors. These include potentially reversible processes such as cell cycle arrest and cellular senescence, as well as apoptotic cell death, which in contrast eliminates dangerous cells that may initiate tumor development. Tumor suppressive processes are organized as complex, extensive signaling networks, controlled by central "nodes.

Endogenous Bcl-xL is essential for Myc-driven lymphomagenesis in mice.

Impaired apoptosis is a cancer hallmark, and some types of lymphomas and other cancers harbor mutations that directly affect key cell death regulators, such as Bcl-2 family members. However, because the majority of tumors seem to lack such mutations, we are examining the hypothesis that tumorigenesis can be sustained at least initially by the normal expression of specific endogenous pro-survival Bcl-2 family members. We previously demonstrated that the lymphomagenesis in Εμ-myc transgenic mice, which constitutively overexpress the c-Myc oncoprotein in B-lymphoid cells and develop pre-B and B-cell lymphomas, does not require endogenous Bcl-2.

Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death.

Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in gamma-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis.