Preferred Label : Granzyme A Mediated Apoptosis Pathway;
Alternative definition : BIOCARTA: One mechanism used by cytotoxic T cells to kill tumor cells and virus-infected
cells is the release of perforin and granzyme proteins. Perforin proteins form pores
in the membranes of the attacked cell, allowing the entry of Granzyme A and Granzyme
B. Granzyme B induces caspase activation and cleavage of factors like ICAD, releasing
DFF40 to fragment DNA, one of the hallmarks of apoptotic cell death. Granzyme A is
also an abundant granzyme released by cytotoxic T cells and is important in cytotoxic
T cell induced apoptosis, activating caspase independent pathways. Once in a cell,
Granzyme A activates DNA nicking by the recently identified DNAse NM23-H1, a tumor
suppressor gene product whose expression is reduced in transformed, metastatic cells.
The previous identification of NM23-H1 as a tumor suppressor indicates that its DNAse
activity plays an important role in immune surveillance to prevent cancer through
the induction of tumor cell apoptosis. The activation of NM23-H1 occurs indirectly,
through the cleavage of proteins that inhibit NM23-H1 in the SET complex, which includes
SET, Ape1, pp32 and HMG2. SET is a substrate for the Granzyme A protease, and SET
cleavage relieves NM23-H1 inhibition to cause apoptotic DNA degradation. In addition
to inhibiting NM23-H1, SET has nucleosome assembly activity and also may help the
interaction of transcriptional regulation with chromatin structure by interacting
with the transcriptional coactivator CBP. The targets of Granzyme A found in the SET
complex also have other important functions. Ape1 repairs oxidative DNA damage, reduces
transcription factors involved in immediate early responses, and its cleavage by Granzyme
A may contribute to DNA degradation and apoptosis. HMG2 is an acidic chromatin-associated
protein that bends DNA, alters chromatin structure and alters the accessibility of
genes for transcription. In addition to acting as a nucleosome assembly factor and
an inhibitor of NM23-H1, SET inhibits DNA and histone methylation by the CBP transcriptional
coactivator. The tumor suppressor pp32 is not cleaved by Granzyme A but is part of
the SET complex. Other targets of Granzyme A include nuclear lamins responsible for
maintaining nuclear structure and histones, the basic building blocks of chromatin
structure. The common involvement of the proteins of the SET complex in chromatin
structure and DNA repair suggest that they work together to protect chromatin and
DNA structure and that inactivation of the complex contributes to apoptosis by blocking
the maintenance of DNA and chromatin structural integrity. (This definition may be
outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_setPathway;
Origin ID : C39230;
UMLS CUI : C1512273;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
