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A historical overview of protein kinase PKR… disrupts the interaction of the PKR-Hsp90-p23 complex,
allowing PKR activation (1, 2). It has been suggested that
3.2. PKR modulation by cellular components Hsp90 contributes to chemotherapy resistance, and its
inhibition has potential therapeutic interest. Similar to
Other functions of PKR (apart from its antiviral Hsp90, Hsp70 binds to PKR, inhibits PKR
activity) have surfaced with the discovery of numerous phosphorylation, and prevents apoptosis (120). In stressed
proteins and other cellular structures modulating the cells, Hsp70 binds to the Fanconi anemia complementation
kinase. Moreover, some cellular proteins also modulate group C (FANCC) protein and forms a ternary complex
PKR to regulate the antiviral and immunomodulatory with PKR (1, 2). Consequently, hematopoietic cells with
responses. FANCC mutations or downregulated Hsp70 show
constitutive PKR activation and sensitivity to various cell
p58IPK. A member of the tetratricopeptide repeat stress signals as well as to IFN-based therapy (121).
family, p58IPK is was the first reported cellular inhibitor Overall, the evaluation of HSPs in cells with different
of PKR (110). p58IPK interacts directly with PKR and basal levels of PKR activation may open an interesting
inhibits its kinase activity by preventing dimerisation. field of study on the regulation of PKR and its therapeutic
Influenza virus partially evades the host's antiviral modulation.
response by recruiting p58IPK to repress PKR-mediated
eIF-2a phosphorylation (1, 2, 111). In the absence of viral NPM. Nucleophosmin (NPM; also known as B23) is
infection, p58IPK overexpression results in malignant an abundant and ubiquitously expressed nucleolar
transformation. Although the exact mechanism has not phosphoprotein implicated in ribosome biogenesis (1,
been defined, it has been suggested that p58IPK 122). It binds nucleic acids, has intrinsic RNase activity
transforms cells by interfering with PKR-regulated and also acts as a molecular chaperone shuttling between
pathways. PKR inhibition by p58IPK can stimulate cell the nucleus and cytoplasm. NPM has also been implicated
growth by disrupting PKR-dependent control of mRNA in the acute response to environmental stress and controls
translation and by blocking PKR-dependent apoptosis (1, cell proliferation (1, 2). NPM is frequently overexpressed
112). Interestingly, an independent antiviral link has in tumours of diverse origin (123), and it is translocated in
recently been identified between both proteins, PKR and lymphomas and leukemias. NPM interacts with PKR,
p58IPK, involving joint degeneration in mice (113). inhibiting eIF-2a phosphorylation and PKR-mediated
apoptosis (124). It was suggested that the capacity of NPM
PACT. The first protein described as PKR activator to inhibit PKR activation could explain how NPM
was PACT (PKR activating protein) able to activate PKR promotes cell proliferation and suppresses the apoptosis
in response to several stresses (1, 23, 24, 72). PACT is a pathway (1). We have identified a novel function for NPM
ubiquitously expressed protein that belongs to the family involving PKR activity with important antitumour and
of dsRNA-binding proteins and has three dsRNA-binding antiviral consequences, as we analyse in the next section.
domains. Although most studies show that PACT is
necessary for PKR activation in response to different toxic 3.3. PKR regulation by miRNAs
compounds, such as arsenic, H2O2, and tunicamycin,
PACT-knockout cells and mice did not exhibit significant The first miRNA identified acting on PKR is the
differences in the response to stressful stimuli compared to noncoding RNA (pre-miR-886) called nc886 (125, 126).
a wild-type phenotype (114). Recently, a possible role of MiRNAs, small noncoding regulatory factors 18–25 nt in
PACT as an inhibitor of PKR during HIV-1 replication has length, could affect gene expression leading to
been described (115). translational and transcriptional regulation of numerous
genes and consequently affect protein expression including
TRBP. Trans-activation response RNA-binding protein kinases. MiRNAs have crucial roles in diverse biological
(TRBP) is a potent PKR modulator that, in turn, regulates processes, including apoptosis and cell growth. Multiple
PACT protein. TRPB has generated great interest because studies have reported altered miRNA levels in stressed
of its role in RNA interference and microRNA (miRNA) cells or in various disease states, including cancer and
processing (116). Since TRBP inhibits PACT and PKR neurodegenerative pathologies. Because of its stability and
activation, both modulators are under intensive analysis as easy detection in body fluids, they are being explored as
potential therapeutic targets. TRBP is a cellular RNA- important biomarkers in various diseases. The extent of
binding protein isolated by its ability to bind human miRNA involvement in PKR regulation and activity is still
immunodeficiency virus type 1 (HIV-1) TAR RNA (117, not fully understood, but studies have begun to identify
118). Proposed TRBP functions include inhibition of PKR miRNA-mRNA targets of kinases involved in different
activation, regulation of cell proliferation, PKR- pathologies. The pre-microRNA nc886 suppresses PKR
independent translational activation, modulation of HIV-1 via direct physical interaction, whereas artificial
gene expression through its association with TAR, and the suppression of nc886 in cholangiocyte cells activated the
control of mRNA translation. TRBP and PKR form a canonical PKR/eIF2a cell death pathway (126). The
complex using direct protein-protein interaction through importance of the detection of nc886 has been recently
their dsRBDs that prevents PKR activation (116). revealed in two studies with oncologic patients where
nc886 levels in the tumour were related with the
Chaperones. Chaperones are PKR modulators that progression of the disease (127). Methylation studies
have a spectrum of inhibitors currently being tested in
preclinical studies with promising expectations (119). PKR 153
is negatively regulated by the heat-shock protein 90
(Hsp90). The drug geldanamycin, an inhibitor of Hsp90,
@Real Academia Nacional de Farmacia. Spain
