Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-02-09
2000-05-09
Sisson, Bradley L.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 78, 435 23, C12Q 168, C12Q 137, G01N 33573
Patent
active
060602384
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a protease that is an effector component of a mammalian cell death pathway. More specifically, it relates to a nucleic acid molecule encoding the protease, the recombinantly produced protease, purified protease and use of the protease. It also relates to methods for regulating apoptosis in a population of cells.
BACKGROUND OF THE INVENTION
Apoptosis, or programmed cell death (PCD), is of fundamental importance to biological processes including embryogenesis, maintenance of tissue homeostasis, normal cellular development of multicellular organisms, elimination of virus-infected cells, and the development of the immune system (Ellis et al. (1991) Ann. Rev. Cell Biol. 7:663-698). It is a type of cell death that is fundamentally distinct from degenerative death or necrosis in that it is an active process of gene-directed cellular self-destruction which in some instances, serves a biologically meaningful homeostatic function. Necrosis, in contrast, is cell death occurring as the result of severe injurious changes in the environment of infected cells. For a general review of apoptosis, see Tomei, L. D. and Cope, F. O. Apoptosis: The Molecular Basis of Cell Death (1991) Cold Spring Harbor Press, N.Y.; Tomei, L. D. and Cope, F. O. Apoptosis II: The Molecular Basis of Apoptosis in Disease (1994) Cold Spring Harbor Press, N.Y.; and Duvall and Wyllie (1986) Immun. Today 7(4):115-119.
Morphologically, apoptosis is characterized by the rapid condensation of the cell with preservation of membranes. Synchronistically with the compaction of chromatin, several biochemical changes occur in the cell. Nuclear DNA is cleaved at the linker regions between nucleosomes to produce fragments that are easily demonstrated by agarose gel electrophoresis wherein a characteristic ladder develops.
Numerous triggers for apoptosis have been identified that induce cell death. The Fas antigen (CD95/APO-1) is a member of the tumor necrosis factor (TNF) receptor superfamily. It is a transmembrane protein with wide tissue distribution. Fas triggers apoptosis upon activation when bound to its ligand or to agonistic anti-Fas antibodies. Cytotoxic T-lymphocytes activate Fas on target cells, inducing cytolysis. TNF also is known to induce apoptosis when cross-linked by its ligand or an agonist antibody.
In addition to being linked to the many biological processes identified above, apoptosis also occurs as a result of human immunodeficiency virus (HIV) infection of CD4.sup.+ T lymphocytes (T cells). Indeed, one of the major characteristics of AIDS is the gradual depletion of CD4.sup.+ T lymphocytes during the development of the disease. Several mechanisms, including apoptosis, have been suggested to be responsible for the CD4 depletion. The depletion of CD4.sup.+ T cells results in the impairment of the cellular immune response. It has been proposed that an inappropriate activation-induced T cell PCD causes the functional and numerical abnormalities of T.sub.H cells from HIV-infected patients, that leads to the near collapse of the patient's immune system. The mechanism by which the Fas antigen initiates the apoptotic cascade, and its various components, remains to be fully elucidated. However, this invention has identified several components of the apoptotic cascade and methods to modulate apoptosis.
SUMMARY OF THE INVENTION
This invention provides non-naturally occurring and isolated, naturally occurring nucleic acid molecules (polynucleotides) which encode proteins designated Yama, Pro-Yama, activated Yama, p20 Yama, p 11 Yama and mutant Yama.
This invention also provides a recombinant nucleic acid molecule having a nucleic acid molecule sequence as shown in FIG. 1. (SEQ. ID. NO: 1) Further provided by this invention are fragments of the above-mentioned nucleic acid molecules. In one embodiment, the fragments have at least 8 nucleic acid bases for use as probes or primers. Specific examples of these fragments are nucleic acid molecules coding for the polypeptides designated herein as p20 Yama and p
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Bugaisky Gabriele E.
Konski Antoinette F.
Sisson Bradley L.
The Regents of the University of Michigan
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