導讀： 簡介: 封面圖 :內容簡介內行的看名字就知道了,我就不寫什麼簡介了,文字版的.也是剛開始看,一知半解.springer的書,一直都很好!以下是書中的Preface:The current year (2004) marks the Silver Annivers 簡介:
封面圖 :


內容簡介
內行的看名字就知道了,我就不寫什麼簡介了,文字版的.也是剛開始看,一知半解.springer的書,一直都很好!以下是書中的Preface:
The current year (2004) marks the Silver Anniversary of the discovery of the p53
tumor suppressor. The emerging field first considered p53 as a viral antigen and then
as an oncogene that cooperates with activated ras in transforming primary cells in
culture. Fueling the concept of p53 acting as a transforming factor, p53 expressionwas
markedly elevated in various transformed and tumorigenic cell lines when compared
to normal cells. In a simple twist of fate, most of the studies conducted in those early
years inadvertently relied on a point mutant of p53 that had been cloned from a normal
mouse genomic library. A bona fide wild-type p53 cDNA was subsequently isolated,
ironically, from a mouse teratocarcinoma cell line. A decade after its discovery, p53
was shown to be a tumor suppressor that protects against cancer. It is now recognized
that approximately half of all human tumors arise due to mutations within the p53
gene. As remarkable as this number may seem, it significantly underrepresents how
often the p53 pathway is targeted during tumorigenesis. It is my personal view, as
well as many in the p53 field, that the p53-signaling pathway is corrupted in nearly
100% of tumors. If you are interested in understanding cancer and how it develops,
you must begin by studying p53 and its pathway.
After demonstrating that p53 functions as a tumor suppressor the field exploded
and p53 became a major focus of scientists around the world. Indeed, there were
approximately 300 published studies on p53 by 1990 and at last count there are more
than 30,000 publications. The amount of information on p53 is truly overwhelming
and in a real sense has created subspecialties within the field. It is quite difficult, if
not impossible, to be well versed and up-to-date on all aspects of p53. It is for this
reason that we have decided to consolidate the most important, landmark findings in
one place, hence the purpose of writing this book.
The thought behind putting this book together was to assemble a group of outstanding
scientist who significantly contributed to our understanding of how p53
functions in tumor suppression. By all means this book does not cover all aspects of
p53; rather, it is meant to provide the necessary information to bring a novice up to
speed with the field. This is no small feat as approximately 1,000 manuscripts havebeen published on p53 within just the first three months of this year and there are no
signs of this pace letting up (ISI Web of Knowledge).
The book has been structured to first provide an overview and a historical perspective
into how the p53 field became what it is today and where it may be heading,
as conveyed by Dr. Arnold Levine, the codiscoverer of p53 (Chapter 1). Much has
been learned about how p53 functions from its molecular structure and Dr. Thanos
Halazonetis has reviewed the latestNMRand crystallography data (Chapter 2).Within
this chapter it is important to note that the mutations observed in human cancer do
not happen randomly and that many of these occur at the sites where p53 contacts
DNA or at critical junctures that disrupt DNA binding. The studies on p53 binding to
DNA leads to the chapters on how p53 functions as a tumor suppressor by regulating
gene expression (Chapters 3 and 4). Clearly p53 recognizes specific DNA sequences
and activates a series of downstream target genes. This area is reviewed by Dr.Wafik
El-Deiry who identified a p53 DNA binding consensus site and discovered p21Cip1 as
a p53-regulated gene while working as a postdoctoral fellow in Dr. Bert Vogelstein’s
lab (see Chapter 3). It is also known that p53 selectively turns off the expression of
down stream targets (transrepression), some of which are thought to be required for
cell survival. Our current understanding of how p53 suppresses gene expression is
extensively reviewed by Dr. Maureen Murphy in Chapter 4. Dr. Murphy moved this
area of research from artifact-prone, overexpression assays to the identification of
endogenous genes that are downregulated by p53 and are required for cell viability.
In Chapter 5, Drs. Ettore Appella and Carl Anderson summarize our understanding
of how p53 becomes activated during cell stress, which occurs almost exclusively
by posttranslational modification. The development of site-specific antibodies has
been critical for studying p53 activation and Drs. Appella and Anderson lead the field
in the generation of these reagents. Site-specific antibodies have been instrumental
in determining how phosphorylation and acetylation is regulated and how these
modifications control p53 function.
As indicated above, it is the p53-signaling pathway acting as a whole that suppresses
tumorigenesis. Obviously, perturbations along the pathway could compromise
p53 activity and consequently promote tumor development. In Chapter 6, Dr. Ute Moll
summarizes what mutations have been observed in p53, how they can arise, and how
the pathway may be corrupted without directly affecting p53 itself. It was Dr. Moll
who first observed the mislocalization of wild-type p53 in the cytoplasm of primary
breast cancer cells and subsequently in neuroblastoma cells.With p53 residing in the
wrong subcellular compartment, it no longer functions efficiently to protect against
cancer despite being “normal” and this contributes to tumorigenesis.
A prominent mechanism for regulating p53 levels and activity is the intricate
negative feedback loop that exists between p53 and Mdm2, a protein that is known to
bind p53 and to block its function in multiple ways. How Mdm2 is regulated and in
turn how it negatively regulates p53 is described in excellent detail in Chapter 7 by
Dr. Jamil Momand, who identified Mdm2 as a critical p53 interacting protein while
working as a postdoctoral fellow in Dr. Levine’s lab. Subsequent studies revealed
the existence of a highly related protein termed, MdmX. What is known about howMdmX is expressed and how it functionally interacts with p53 and Mdm2 is also
presented in this chapter. Pay close attention to the elegant genetic studies examining
the phenotypes of Mdm2 and MdmX knockout mice and how these responses are
influenced by p53 status.
Recent work has uncovered highly related p53 family members, specifically p63
and p73, suggesting that p53 may not act alone in suppressing tumor growth. Drs. Elsa
Flores and Tyler Jacks review the literature surrounding the p53 family of proteins
and present some of their latest studies on the consequence of p63 and p73 loss on
cell growth and survival (Chapter 8). Intuitively, the functional interaction that exists
between the family members would suggest an important role for p63 and p73 in
tumor suppression. The consequence of deleting p63 and p73 in knockout mice on
tumor susceptibility remains to be seen and should be enlightening.
The original observations of p53 acting as an oncogene during the time when
most studies were carried out using the mutant form are not incorrect. Clearly, loss
of p53 compromises tumor suppressor function as demonstrated by the finding that
100% of p53-knockout mice develop malignant tumors, usually within several months
of age. Nevertheless, most tumors associated with defects in p53 express a fulllength
missense p53 protein. It is important to keep in mind that the missense protein
is usually expressed at high levels in the nucleus and is not biochemically inert.
The consequence that overexpression of mutant p53 has on tumor cell growth and
survival is not completely understood. What is recognized however is that mutant
p53 has the capability of making matters worse and can actively promote tumorigenesis
through a gain-of-function mechanism. In Chapter 9, Drs. Alex Sigal and
Varda Rotter discuss what is known about mutant p53 tumor promoting properties.
Dr. Rotter is most appropriate to review this area as it was her seminal observations
in the 1980s that provided the first insight into the tumorigenic properties of
mutant.
Lastly, in Chapter 10, Dr. Andrei Gudkov summarizes the current state of affairs
concerning the development of compounds that can restore tumor suppressor function
to mutant p53. Considering that half of all human cancers express a mutant form of
p53, the identification of a small molecule that could correct the biochemical defect
could have a huge clinical impact. Although Iwas skeptical that this could ever happen,
recent work byWiman and coworkers provide a strong indication that this indeed can
be possible. These exciting findings as well as other important studies are reviewed
in this chapter. In addition, there are certain circumstances where p53 activation
can actually be detrimental, such as during stroke, chemotherapy, or neurological
degeneration. Therefore, compounds that inhibit wild-type p53 activity can also be
desirable. Dr. Gudkov has been instrumental on this front and has recently identified a
compound called pifithrin, which is also discussed here.Myintentwas to conclude the
book with this chapter to provide some hope that there are reasonable ways to combat
human cancers and other diseases associated with p53 mutations or perturbations in
its pathway.
There is some redundancy between the chapters and this is unavoidable as each
“subspecialty” overlaps to a degree with one another. Although these areas do overlap
on occasion, the personal views, which are spun on the literature as discussed within
each chapter, provides a rich and much broader understanding of the topic.
Dr. Arnie Levine once said that science moves forward in waves. He said that
uncovering the true function of p53 as a tumor suppressor in 1989 was one such wave
and that therewould be others. Soon thereafter, Dr. Momand identified Mdm2 as a p53
binding protein. It did not take long to prove that Mdm2 was an oncogene because it
blocks p53 function. From this simple observation a subfield was established leading
to the demonstration that Mdm2 is frequently amplified and overexpressed in human
cancers. What the future holds for p53 and the genes that are tied into this extremely
important pathway should bring yet more exciting waves!
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