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Characterization of AJH-836, a diacylglycerol-lactone with selectivity for novel PKC isozymes
Cooke, Mariana,Zhou, Xiaoling,Casado-Medrano, Victoria,Lopez-Haber, Cynthia,Baker, Martin J.,Garg, Rachana,Ann, Jihyae,Lee, Jeewoo,Blumberg, Peter M.,Kazanietz, Marcelo G. American Society for Biochemistry and Molecular Bi 2018 The Journal of biological chemistry Vol.293 No.22
<P>Diacylglycerol (DAG) is a key lipid second messenger downstream of cellular receptors that binds to the C1 domain in many regulatory proteins. Protein kinase C (PKC) isoforms constitute the most prominent family of signaling proteins with DAG-responsive C1 domains, but six other families of proteins, including the chimaerins, Ras-guanyl nucleotide-releasing proteins (RasGRPs), and Munc13 isoforms, also play important roles. Their significant involvement in cancer, immunology, and neurobiology has driven intense interest in the C1 domain as a therapeutic target. As with other classes of targets, however, a key issue is the establishment of selectivity. Here, using [H-3]phorbol 12,13-dibutyrate ([H-3]PDBu) competition binding assays, we found that a synthetic DAG-lactone, AJH-836, preferentially binds to the novel PKC isoforms PKC and PKCE relative to classical PKC and PKCII. Assessment of intracellular translocation, a hallmark for PKC activation, revealed that AJH-836 treatment stimulated a striking preferential redistribution of PKCE to the plasma membrane relative to PKC. Moreover, unlike with the prototypical phorbol ester phorbol 12-myristate 13-acetate (PMA), prolonged exposure of cells to AJH-836 selectively down-regulated PKC and PKCE without affecting PKC expression levels. Biologically, AJH-836 induced major changes in cytoskeletal reorganization in lung cancer cells, as determined by the formation of membrane ruffles, via activation of novel PKCs. We conclude that AJH-836 represents a C1 domain ligand with PKC-activating properties distinct from those of natural DAGs and phorbol esters. Our study supports the feasibility of generating selective C1 domain ligands that promote novel biological response patterns.</P>
Cooke, Fadzilah Majid,Hussin, Rosazman Korea Institute for ASEAN Studies 2014 Suvannabhumi Vol.6 No.2
With natural resources-terrestrial or coastal-fastly diminishing, governments are now resorting to biodiversity conservation, fast-tracking the introduction of new legislations, as well as the amendment of existing ones, and laying out programs that interpret existing practices and research agendas. This paper examines how biodiversity conservation-in addition to eco-tourism-has become an important symbol of the modernizing state of Sabah, Malaysia. It further examines the effects of biodiversity conservation on state and community management of natural resources, with particular reference to the management of natural resources by the indigenous peoples of Sabah. Citing case studies and focusing on a forest community at Kiau Nuluh, in the district of Kota Belud, Sabah, this paper evaluates strategies used by indigenous groups to maintain access and control over the management of natural resources-and by implication to livelihoods-via ecotourism, making creative alliances with non-government organisations as well as forging cooperation with government agencies which act as custodians of these resources. For a majority of indigenous groups however, the practice of biodiversity conservation has meant reduced and controlled access to natural resources, considering the fundamental issue of the lack of security of tenure to the land claimed under customary rights. New initiatives at recognizing Indigenous and Community Conserved Areas (ICCAs) by international conservation groups provide a means for tenure recognition, for a price, of course. The recognition of ICCAs also faces obstacles arising from developmentalist ideology which upholds that forests are valuable only when converted to other land use, and not left to stand for their intrinsic value.
Fadzilah Majid Cooke,Rosazman Hussin 부산외국어대학교 아세안연구원 2014 Suvannabhumi Vol.6 No.2
With natural resources—terrestrial or coastal—fastly diminishing, governments are now resorting to biodiversity conservation, fast-tracking the introduction of new legislations, as well as the amendment of existing ones, and laying out programs that interpret existing practices and research agendas. This paper examines how biodiversity conservation—in addition to eco-tourism—has become an important symbol of the modernizing state of Sabah, Malaysia. It further examines the effects of biodiversity conservation on state and community management of natural resources, with particular reference to the management of natural resources by the indigenous peoples of Sabah. Citing case studies and focusing on a forest community at Kiau Nuluh, in the district of Kota Belud, Sabah, this paper evaluates strategies used by indigenous groups to maintain access and control over the management of natural resources—and by implication to livelihoods—via ecotourism, making creative alliances with non-government organisations as well as forging cooperation with government agencies which act as custodians of these resources. For a majority of indigenous groups however, the practice of biodiversity conservation has meant reduced and controlled access to natural resources, considering the fundamental issue of the lack of security of tenure to the land claimed under customary rights. New initiatives at recognizing Indigenous and Community Conserved Areas (ICCAs) by international conservation groups provide a means for tenure recognition, for a price, of course. The recognition of ICCAs also faces obstacles arising from developmentalist ideology which upholds that forests are valuable only when converted to other land use, and not left to stand for their intrinsic value.
DAZL is essential for stress granule formation implicated in germ cell survival upon heat stress
Kim, B.,Cooke, H. J.,Rhee, K. The Company of Biologists 2012 Development (Cambridge) Vol.139 No.3
<P>Mammalian male germ cells should be maintained below body temperature for proper development. Here, we investigated how male germ cells respond to heat stress. A short exposure of mouse testes to core body temperature induced phosphorylation of eIF2α and the formation of stress granules (SGs) in male germ cells. We observed that DAZL, a germ cell-specific translational regulator, was translocated to SGs upon heat stress. Furthermore, SG assembly activity was significantly diminished in the early male germ cells of Dazl-knockout mice. The DAZL-containing SGs played a protective role against heat stress-induced apoptosis by the sequestration of specific signaling molecules, such as RACK1, and the subsequent blockage of the apoptotic MAPK pathway. Based on these results, we propose that DAZL is an essential component of the SGs, which prevent male germ cells from undergoing apoptosis upon heat stress.</P>