Current Molecular Medicine
The Promise and Obstacle of p53 as a Cancer
Therapeutic Agent Pp.329-345
A.C.
Willis and X. Chen
Malignant Hyperthermia: A Pharmacogenetic
Disease of Ca++ Regulating Proteins Pp.347-369
Thomas
E. Nelson
Critical Role for IL-15 in Innate Immunity Pp.371-380
Toshiaki
Ohteki
The Role of STATs in Apoptosis Pp.381-392
T.E.
Battle and D.A. Frank
Immunity to Systemic Salmonella Infections Pp.393-406
Pietro
Mastroeni
[Back to top] The Promise and Obstacle of p53 as a Cancer
Therapeutic Agent
A.C. Willis and X. Chen
p53 is a tumor
suppressor gene that is mutated in greater than 50% of human cancers. The
action of p53 as a tumor suppressor involves inhibition of cell proliferation
through cell cycle arrest and/or apoptosis. Loss of p53 function therefore
allows the uncontrolled proliferation associated with cancerous cells. While
design of most anti-cancer agents has focused on targeting and inactivating
cancer promoting targets, such as oncogenes, recent attention has been given to
restoring the lost activity of tumor suppressor genes. Because the loss of p53
function is so prevalent in human cancer, this protein is an ideal candidate
for such therapy.
Several gene
therapeutic strategies have been employed in the attempt to restore p53
function to cancerous cells. These approaches include introduction of wild-type
p53 into cells with mutant p53; the use of small molecules to stabilize mutant
p53 in a wild-type, active conformation; and the introduction of agents to
prevent degradation of p53 by proteins that normally target it. In addition,
because mutant p53 has oncogenic gain of function activity, several approaches
have been investigated to selectively target and kill cells harboring mutant
p53. These include the introduction of mutant viruses that cause cell death
only in cells with mutant p53 and the introduction of a gene that,in the
absence of functional p53, produces a toxic product. Many obstacles remain to
optimize these strategies for use in humans, but, despite these, restoration of
p53 function is a promising anti-cancer therapeutic approach.
[Back to top] Malignant Hyperthermia: A Pharmacogenetic
Disease of Ca++ Regulating Proteins
Thomas E. Nelson
Malignant
hyperthermia (MH) is a pharmacogenetic, life-threatening hypermetabolic
syndrome in genetically predisposed individuals exposed to certain anesthetic
agents. Discovered by Denborough and Lovell [1] in 1960, MH was associated with
high mortality and morbidity as the cause was unknown and an effective
treatment was unavailable. There is no classic clinical presentation of the
syndrome, and the onset and signs of MH are dependent upon known and unknown
environmental and genetic factors. Initial theories involved central
temperature regulation defects or uncoupling of oxidative phosphorylation in
mitochondria [2], but later investigations targeted skeletal muscle as the
affected organ. Subsequently freshly biopsied skeletal muscle was used for in
vitro pharmacologic contracture testing to discriminate between normal and
MH-affected muscle and remains the “gold standard” for MH diagnosis.
Spontaneous, genetic models for MH were discovered in pigs and dogs and
substantial knowledge about MH was gained from these valuable resources. The
abnormal contracture response of MH skeletal muscle evoked a focus on calcium
regulation, and abnormalities in calcium release (as opposed to calcium
sequestration) mechanisms were discovered. About this same time the major
calcium release channel in the skeletal muscle sarcoplasmic reticulum membrane
was purified and named the ryanodine receptor [3]. Although the ryanodine
receptor represents one of the largest functional proteins, the enormous gene
encoding the 5021 amino acids comprising the ryanodine receptor subunit was
eventually cloned [4,5]. Patient and dedicated work on the ryanodine receptor
gene has found linkage to MH in the pig [6], dog [7], and among several
different mutations and MH in unrelated human families [8,9]. Expression of
these mutations in HEK cells has resulted in abnormal calcium release [10,11],
supporting but not proving a causal basis for MH. In this review each of the
areas mentioned above is discussed in detail revealing a wonderful success
story that changed the anesthesiologist’s “worst nightmare” from a syndrome
with high mortality and morbidity to a reasonably well managed disease today.
This success story includes unraveling the molecular basis for the disease and
brings its pathoetiologic and diagnostic aspects toward molecular genetic
resolution.
[Back to top] Critical Role for IL-15 in Innate Immunity
Toshiaki Ohteki
Although some
functional activities of interleukin (IL)-15 on NK and T cells overlap with
those of IL-2, recent findings obtained from gene-targeted mice deficient in
components of IL-2/IL-15 system demonstrate distinct roles of IL-15 for the
activation of innate immune system. IL-15 is a pivotal cytokine for the
development and survival of NK cells, NKT cells, TCRgd+
intestinal intraepithelial lymphocytes (iIEL), and for the functional
maturation of dendritic cells and macrophages. IL-15 is also important for
memory T cell maintenance in vivo. In this review, I summarize recent progress
of studies in the IL-15/IL-15R system.
[Back to top] The Role of STATs in Apoptosis
T.E. Battle and D.A. Frank
Signal transducers and activators of transcription (STATs) are transcription factors that mediate cytokine and growth factor induced signals that culminate in various biological responses, including proliferation and differentiation. Recent studies indicate a role for STATs in apoptosis as well. Depending upon the particular stimulus or cell type, STATs can mediate either pro-apoptotic signals or anti-apoptotic signals. STAT1 and, under some circums-tances, STAT3 are important for transducing pro-apoptotic signals whereas STAT3 and STAT5 have been implicated in promoting cell survival. Recent studies demonstrate that regulation of apoptotic pathways by STATs is largely due to transcriptional activation of genes that encode proteins that mediate or trigger the cell death process, such as Bcl-xL, caspases, Fas and TRAIL as well as those that regulate cell cycle progression, such as p21waf1. Interestingly, STAT proteins may also regulate apoptosis through a non-transcriptional mechanism by inhibiting the anti-apoptotic protein NF-kB. Considering that dysregulation of the STAT signaling pathway is commonly found in clinical tumor samples, understanding the mechanisms underlying STAT regulation of cell survival may lead to successful strategies for targeting STATs in cancer therapy.
[Back to top] Immunity to Systemic Salmonella Infections
Pietro Mastroeni
Salmonella infections
are a serious public health problem in developing countries and represent a
constant concern for the food industry. The severity and the outcome of a
systemic Salmonella infection depends on the “virulence” of the bacteria, on
the infectious dose as well as on the genetic makeup and immunological status
of the host. The control of bacterial growth in the reticuloendothelial system
(RES) in the early phases of a Salmonella infection relies on the NADPH
oxidase-dependent anti-microbial functions of resident phagocytes and is
controlled by the innate resistance gene Nramp1. This early phase is followed
by the suppression of Salmonella growth in the RES due to the onset of an
adaptive host response. This response relies on the concerted action of a number
of cytokines (TNFa, IFNg, IL12, IL18, and IL15), on the recruitment
of inflammatory phagocytes in the tissues and on the activation of the
recruited cells. Phagocytes control bacterial growth in this phase of the
infection by producing reactive nitrogen intermediates (RNI) generated via the
inducible nitric oxide synthase (iNOS). Clearance of the bacteria from the RES
at a later stage of the infection requires the CD28-dependent activation of CD4+
TCR-ab T-cells and is controlled by MHC class II
genes. Resistance to re-infection with virulent Salmonella micro-organisms
requires the presence of Th1 type immunological memory and anti-Salmonella
antibodies. Thus, the development of protective immunity to Salmonella
infections relies on the cross-talk betwee the humoral and cellular branches of the immune system.