Isolation of genes controlling apoptosis through their effects on cell survival - Research article (original) (raw)

Isolation of genes controlling apoptosis through their effects on cell survival

Gene therapy & molecular biology, 2006

The identification of the most suitable molecular targets for gene and drug therapy is the crucial first step in the development of new disease treatments. The rational identification of such targets depends on a detailed understanding of the pathological changes occuring at the molecular level. We have applied forward genetics approaches to the identification of the critical genes involved in the control of apoptosis in mammalian cells, since defective control of apoptosis underlies many diseases, including cancer and neurodegenerative diseases. We have identified two groups of genes by their effects on cell survival using retroviral cDNA functional expression cloning and retroviral insertional mutagenesis. The identification of these novel genes opens up new areas for apoptosis research and subsequently for the development of new gene and drug therapies.

Genealogy, expression, and molecular mechanisms in apoptosis

Pharmacology & therapeutics, 2004

Apoptosis, known as programmed cell death, is a conserved, gene-directed mechanism for the elimination of unnecessary or unwanted cells from an organism. A retrospective look at the basis of human disease pathogenesis almost always reveals an apoptotic component that either contributes to disease progression or accounts for it. Modulating the expression of key molecular components of the cell death machinery is an attractive and obvious strategy for apoptosis-based therapeutics. Apoptosis is an important component of most developmental abnormalities and human diseases and in many cases the underlying cause of the resulting pathology. It has also become clear that many, if not all, viruses possess mechanisms to forestall apoptosis and provide a living host to enhance virus propagation. Diseases like AIDS involve excessive apoptosis, and suppression of apoptosis may restore functionality to the infected tissues. Although these are still early days, it is difficult not to get excited about the significant advances that have already been made. The true therapeutic benefits of apoptosis modulation for the treatment of many devastating human diseases remain to be discovered.

Molecular and clinical aspects of apoptosis

Pharmacology & Therapeutics, 1996

Unwanted cells are removed by physiological cell death processes that are highly conserved throughout the animal kingdom. Physiological cell death plays an important role in development, tissue homeostasis and defence against viral infection and mutation. This review describes the molecular components that implement this process, the relevance of these to a variety of human diseases, and discusses the potential for novel therapies based on our understanding of them.

Major apoptotic mechanisms and genes involved in apoptosis

Tumor Biology, 2016

As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

Apoptosis: Molecular mechanism

Journal of Orofacial Sciences, 2012

Cell death is one of the essential processes. Balance between cell division and cell death is of utmost importance for the development and maintenance of multi-cellular organism. Disorders of either process have pathologic consequences and can lead to disturbed embryogenesis, neurodegerative diseases, or the development of cancers. This article reviews the apoptotic as well as anti-apoptotic molecules along with molecular pathways, which may alter in many diseases.

Apoptosis in health and disease and modulation of apoptosis for therapy: An overview

Indian Journal of Clinical Biochemistry, 2007

Apoptosis a physiological mechanism that eliminates excessive, damaged or unwanted cells, is a highly regulated pathway important for maintaining homeostasis in multicellular organisms. It can be initiated through various signals via the extrinsic pathway which involves death receptors, or via the intrinsic pathway which is initiated by intracellular damage and involves the mitochondria and release of cytochrome c from it to further activate caspases. The Bcl-2 family of proteins is situated upstream to the irreversible damage of cellular constituents and is an important checkpoint in the fate of a cell. The pro-apoptotic members, BH3 only members include BID, BAD and BIM. They directly or indirectly activate multidomain BAX/ BAK that constitute the requisite gateway to the intrinsic pathway which operates at the mitochondrial surface and endoplasmic reticulum. In contrast, antiapoptotic members such as Bcl-2, Bcl-XL bind and sequester activation. Downstream of mitochondria, the apoptosome involvement is seen to generate caspase activity. Post mitochondria regulation involves IAPs, and their inhibitors. The pathogenesis of several diseases such as cancer, neurodegenerative disorders, autoimmune disorders, heart disease, infectious diseases including AIDS is closely related to aberrant apoptosis. Consequently interest has emerged in employing various therapeutic approaches such as gene therapy, antisense therapy, recombinant biologicals, organic and combinatorial chemistry, to specifically target apoptosis signaling pathways such as death receptors FAS/TRAIL, p53, IAPs, SMAC and caspases, etc. and are now advancing from preclinical to clinical phase.

Apoptosis, guardian of the genome: Review

Zenodo (CERN European Organization for Nuclear Research), 2021

Apoptosis has attracted great attention in the last two decades and the number of publications related to apoptosis has been growing exponentially. The revolution that has occurred in apoptosis research is a direct result of a better understanding of the genetic program and biochemical mechanisms of apoptosis. Apoptosis is not only a common normal event but also essential for the growth and development of organisms. In the adult, apoptosis is mostly abnormal, but in its absence or failure cancer cells obtain immortality by escaping this type of cell death. Apoptosis works synergistically in intrinsic and extrinsic pathways. The first pathway is initiated by the cell itself in response to stress. The second is initiated via death receptors stimulated by cells of the immune system. This review is an attempt to answer questions like: Why is cell death important to study? How cells undergo apoptosis? What controls the decision between life and death? Which cellular events could cause the control of apoptosis to be impaired? The literature cited below shows some sort of unity in the scientific community on the necessity of a sophisticated balance between "prosurvival" and "pro-death" forces to ensure the happiness of cells in multicellular organisms

Modulating apoptosis as a target for effective therapy

Molecular Immunology, 2006

Alterations in cell proliferation and cell death are essential determinants in the pathogenesis and progression of several diseases such as cancer, neurodegenerative disorders or autoimmune diseases among others. Complex networks of regulatory factors determine whether cells proliferate or die. Recent progress in understanding the molecular changes offer the possibility of specifically targeting molecules and pathways to achieve more effective and rational therapies.

Biochemical and molecular mechanisms regulating apoptosis

Molecular and cellular biochemistry, 1998

In eukaryotes, the regulation of tissue cell numbers is a critical homeostatic objective that is achieved through tight control of apoptosis, mitosis and differentiation. While much is known about the genetic regulation of cell growth and differentiation, the molecular basis of apoptosis is less well understood. Genes involved in both cell proliferation and apoptosis reflect the role of some stimuli in both of these processes, the cell response depending on the overall cellular milieu. Recent research has given fascinating insights into the complex genetic and molecular mechanisms regulating apoptosis. A picture is emerging of the initiation in certain cells, after an apoptotic trigger, of sequential gene expression and specific signal transduction cascades that guide cells along the cell death pathway. Changes in gene expression precede the better known biochemical and morphological changes of apoptosis. It seems possible that, as a result of increased understanding of the cellular...

The proteins and the mechanisms of apoptosis: a mini-review of the fundamentals

Hippokratia, 2007

Apoptosis or programmed cell death is a physiological mechanism, characterized by specific morphological and biochemical changes such as cell shrinkage, chromatin condensation, protein cleavage, DNA breakdown and phagocytosis. Apoptosis is a significant contributor to the morphologic and functional development of multicellular organisms. It is also involved in the pathogenesis of several diseases including degenerative diseases of the central nervous system (CNS) like Alzheimer's disease or Parkinson's disease, cancer and immune system dysfunction. There are many factors, mainly proteins, which are involved in the activation, regulation and execution of related events. A fairly detailed outline of apoptotic mechanisms has also started to emerge and to be verified. In this short, focused mini-review, we attempt to outline current evidence regarding the mechanisms and the regulation of apoptosis.