RESUMO
Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2.
Assuntos
Mitocôndrias/metabolismo , NADH Desidrogenase/genética , Estresse Oxidativo/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Células A549 , Animais , Apoptose/genética , Respiração Celular/genética , Citosol/metabolismo , Drosophila melanogaster/genética , Complexo I de Transporte de Elétrons/genética , Humanos , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Transdução de Sinais/genéticaRESUMO
INTRODUCTION: Monoclonal antibody (mAb)-based products are highly specific for a particular antigen. This characteristic feature of the molecules makes them an ideal tool for many applications including cancer diagnosis and therapy. SOURCES OF DATA: We performed comprehensive searches of PubMed, Medline and the Food and Drug Administration website using keywords such as 'therapeutic antibodies' and 'anti-cancer antibodies'. AREAS OF AGREEMENT: Treatment of cancer patients with antibodies when used alone or in combination with chemotherapy and radiotherapy, or conjugated to drugs or radioisotopes, prolongs overall survival in cancer patients. Currently, there are 14 mAb-based drugs that have been approved for the treatment of cancer patients. AREAS OF CONTROVERSY: The response of cancer patients to antibody therapy can be of short duration. Therapeutic antibodies are expensive and may have side effects. There are no reliable predictive biomarkers for sensitivity or resistance to certain therapeutic antibodies. FUTURE FOCUS: There should be additional studies to discover novel therapeutic targets, to develop more effective antibody-based drugs with fewer side effects, to identify more reliable predictive biomarker(s) for response to therapy with antibody-based drugs and to develop alternative strategies (e.g. transgenic plants, transgenic farm animals) for production of large quantities and more affordable batches of therapeutic antibodies. AREAS TIMELY FOR DEVELOPING RESEARCH: A better understanding of cancer biology, the hallmarks of human cancers and the immune system would lead to identification of additional cell surface biomarkers. These in turn would facilitate the development of novel and biosimilar antibody-based drugs and their routine use as 'magic bullets' for the targeted therapy of human cancers.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias/terapia , Animais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores , Humanos , Hibridomas , Neoplasias/diagnósticoRESUMO
The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as adenosine triphosphate (ATP) synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside in or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by guanosine triphosphatases (GTPases) on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis, regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover, and this review will discuss these mechanisms required for correct mitochondrial network organization.