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Originally published In Press as doi:10.1074/jbc.R200013200 on June 5, 2002
J. Biol. Chem., Vol. 277, Issue 30, 26709-26716, July 26, 2002
REFLECTIONS
Regulation, Restriction, and Reminiscences
Arthur B.
Pardee
From the Dana-Farber Cancer Institute,
Boston, Massachusetts 02115
 |
INTRODUCTION |
Choose a job you love,
and you will never have to work a day in your
life Confucius
These reflections cover more than 60 years of my
research, selected from among those that I consider to be of greatest
scientific interest. It is a personal account, not a general review of
all contributions, and so I have not included the numerous references into which my contributions are imbedded. I regret that I could not
include other topics and colleagues. Some details, anecdotes, etc. are
described in my previous reviews and overviews.
Subjects of my research may appear to be quite diverse. This is because
from childhood I was fascinated by reading about explorers of new
territories. They are my heroes, rather than the developers who came
later. So in science my goal is always to explore new questions. There
is, however, a central theme: the molecular basis of regulation. It can
be observed at all levels of biological complexity. The goal and theme
that bind together the disparate subjects of my investigation are to
gain understanding of the general molecular mechanisms that underlie
regulatory processes and their defects in diseases, principally in cancer.
| |
Beginnings |
Biological science has changed dramatically since I began
research. One can liken the evolution of techniques to slide rules becoming computers. My undergraduate training was in chemistry at
University of California, Berkeley (1938-1942), where I was fortunate
in being taught by Nobel laureates William Giaque (freshman chemistry)
and Melvin Calvin (undergraduate research). I did my Ph.D. under Linus
Pauling at the California Institute of Technology (1942-1947),
performing some of the first studies with purified antibodies. I was
pretty cheeky; when Pauling noted that a graduate student should know
how to spell "phenolpthalein," I noted back that "so
should a professor." Graduate studies were interrupted by World War
II, during which I performed research on chemical warfare agents and
then on uranium, learning very directly about toxic substances and
radioactivity, respectively. The death of my mother in 1942 directed me
toward doing what I could against cancer, so I then took a Merck
postdoctoral fellowship with Van Potter at the University of
Wisconsin (1947-1949). His research was on deregulation in cancers of
oxidative phosphorylation and the Krebs cycle, studied mainly with
tissue homogenates. I learned a great deal under his wise guidance and
was very productive. However, I decided that the time was not ripe for
me to pursue cancer problems because of my inadequate knowledge of
metabolic pathways, their regulation, and techniques for investigation. Therefore I shifted to more amenable bacterial systems.
I joined the faculty of the biochemistry department and the virus
laboratory at University of California, Berkeley, of which Wendell
Stanley was Director, in 1949. Subsequently I made several novel
discoveries. We, simultaneously with others, discovered ribonucleoprotein particles in bacteria, later named ribosomes, and
also found photosynthetic particles that we called chromatophores (1).
I wanted to learn whether virus infection changes the metabolism of the
host and discovered that nine enzyme activities changed after infection
of Escherichia coli with bacteriophage (2). These included
deoxyribonuclease, suggesting involvement of phage DNA in infection.
Later when we replaced thymidine with bromodeoxyuridine in phage DNA
many mutants were produced, which is consistent with DNA being the
genetic material of the virus (3). This research led to my being chosen
a Young Biochemist in 1953 to represent the United States at the
International Biochemistry Congress in Paris and to tour Europe, both
remarkable experiences.
| |
Regulation of Enzyme Activity |
I first thought about metabolic regulation while I was a
postdoctoral fellow. We demonstrated that oxalacetate inhibits succinic dehydrogenase, several steps back in the Krebs cycle (4). I wondered
whether this "feedback" could keep reactions of the complex cycle
in balance. I initially investigated coordination between molecular
syntheses in E. coli and found linkages: that nucleic acid
precursors are required for protein synthesis (5) and furthermore
nucleic acid synthesis depends on the presence of amino acids (6).
However, concurrent synthesis of DNA was not necessary.
Feedback and Allosteric Inhibition--
Living organisms
usually produce their constituent molecules in amounts sufficient to
meet their needs, no more or less. Is there a general mechanism to
explain this economical metabolic regulation? In 1950 biochemists did
not ask this question; they were very busy creating a map of metabolism
in which all roads were of the same intensity although traffic flow
along some was far greater than on others. Richard Yates and I (and
independently Ed Umbarger) reported a general control mechanism: we for
the pyrimidine pathway and he for the isoleucine-valine biosynthetic pathway. Its principle is similar to regulating heat production of a
furnace by a thermostat. An end product biosynthetic pathway can be an
inhibitor of its initial enzymatic reaction. Thereby, in a living cell
end product in excess economically shuts down its own synthesis. The
feedback mechanism has now been verified for numerous pathways, and it
remains a subject of active investigation (7). Regulation is complex
for some of these, involving branching to produce several end products
as studied by Earl Stadtman or of an enzyme with several substrates
like ribonucleotide reductase as elucidated by Peter Reichard.
The breakthrough came when I was using mutants defective in steps of
the pathway that synthesizes the pyrimidines by seven successive
enzyme-catalyzed reactions. I noticed that the metabolite synthesized
prior to the absent reaction of a mutant accumulated as expected, but
not when I made available the end product of the pathway. This
observation was literally breathtaking, because I perceived that it
suggests a novel mechanism for control of metabolism. Richard Yates and
I reported at a 1954 AAAS meeting that "uracil blocks an enzyme step
between aspartate and ureidosuccinate formation, and this block may be
an important regulatory mechanism in the cell." In three subsequent
papers (8-10) we established this regulation. These discoveries led to
perhaps the first review on regulation of metabolism (11).
Regulatory Sites--
The molecular mechanism of
feedback inhibition immediately created a problem. The general
conception of inhibitors then was that they compete with substrate
quite specifically for binding to an active site of the enzyme. How can
a pyrimidine inhibit the enzyme aspartate transcarbamylase since it is
structurally very dissimilar to the substrates, aspartate and carbamyl
phosphate? I addressed this question after I returned from a sabbatical
in Jacques Monod's laboratory (see below). The uncertainties posed by
results obtained with crude extracts made me decide to first obtain the
pure enzyme, which Margaret Shepherdson and I isolated and
crystallized (12). With this pure enzyme, John Gerhart demonstrated that the inhibitor is the ultimate end product cytidine triphosphate (CTP), which has no structural similarity to the substrates aspartate or carbamyl phosphate (13). An indication of a regulatory site distinct
from the catalytic site was that ATP activates the enzyme in contrast
to the inhibitory CTP (Fig. 1). ATP,
which is not a substrate, evidently cannot bind to the active site
because this would have to be inhibitory, and therefore it must bind to a different, regulatory site.
The key came from an unusual observation. Gerhart kept getting variable
results of inhibition by CTP, although the pure enzyme always had high
catalytic activity. When we examined his data closely we noticed that
inhibition was strong at the beginning of each week and decreased
thereafter. His procedure was that each Monday he thawed an aliquot of
the deep-frozen enzyme and stored it in the refrigerator for later use.
Hypothesizing that the enzyme must change its properties during this
cold storage, he warmed it systematically and found that brief exposure
to 65 °C abolished inhibition by CTP but not catalytic activity.
Thus, we dissociated sites that we named regulatory as distinct from functional ones (14). Gerhart went on to separate the regulatory and
catalytic subunits of the enzyme, later investigated in detail by
physical chemistry and x-ray diffraction.
At the same time, Jean-Pierre Changeux in the laboratory of Monod
investigated the mechanism of feedback inhibition of the isoleucine-valine pathway discovered by Ed Umbarger, and from kinetic studies concluded that there are inhibitory sites in addition to catalytic ones. These may be the first molecular demonstrations of
regulation of protein function by a small molecule. Monod conceived the
generalization of allostery, which he called "the second secret of
life." The two types of binding sites on proteins, one functional and
the other regulatory, permit regulation of any biological reaction by a
process in which a regulatory molecule need have no structural
similarity to the molecules acted upon (15). He combined three lines of
research to create the allosteric concept: (i) feedback inhibition with
regulatory sites; (ii) control of gene expression (see below); and
(iii) cooperative binding of oxygen to the subunits of hemoglobin
(16).
Another major development arising from feedback inhibition is the
finding that enzymes often function in complexes with other proteins
rather than as single proteins, which was then the biochemical concept.
An early example is Prem Reddy's report that DNA synthesis is not
catalyzed by its polymerase acting alone but by a multienzyme complex
that we named "replitase" (17), a finding that initially met with
considerable opposition. It should not have been surprising because
proteins are synthesized by very large multiprotein complexes, ribosomes, and we now know that complexes consisting of RNA polymerase plus regulatory transcription factors synthesize RNA. Reports of
feedback inhibition, regulatory subunits, allosteric sites, and
multiprotein complexes now abound in the literature.
| |
Regulation of Enzyme Expression by Repression |
In addition to regulation of enzyme activity as outlined
above, there evidently was another major regulation that determined amounts of enzymes. Enzyme activities were known to "adapt," to change dramatically, as a function of the nutrients provided to bacteria. This mechanism would provide a coarse control of metabolic regulation relative to fine regulation by feedback inhibition. I began
to investigate such regulatory mechanisms for enzyme synthesis early in
the 1950s (10, 18). When in 1957-1958 I had the opportunity to take a
sabbatical leave I decided to go to the laboratory in Paris of Jacques
Monod, the outstanding investigator of this problem. He studied the
dramatic changes of  -galactosidase activity in E. coli as a function of availability of -galactosides and other carbon sources.
Monod, Francois Jacob, and I discovered the general molecular mechanism
of this process. It is by action of a protein we named the repressor
that specifically blocks gene expression, which is released when a low
molecular weight inducer molecule binds to it. Specifically, expression
of the -galactosidase gene, and two adjacent genes, is inhibited by
a repressor molecule that binds to an upstream operator sequence of the
bacterial DNA. This negative regulation is released by binding of a
-galactoside to an allosteric site of the repressor (19). This has
often been reviewed (15, 20, 21). This research is the basis for current concepts of the major mechanism for regulating gene expressions in both prokaryotes and eukaryotes.
Our investigations of gene expression provided one of the origins for
discovery of messenger RNA. Since the enzyme probably is not made
directly on DNA, we proposed from kinetics an unstable intermediate
between gene and enzyme (22). This was soon thereafter shown by others
to be an RNA. In accord with an unstable intermediate, we then
demonstrated that the enzyme begins to be produced about a minute after
its gene is activated and quickly ceases after the inducer is removed
(23). Monica Riley demonstrated that destruction of the gene by
radioactive decay of incorporated 32P causes cessation of
enzyme synthesis (24).
| |
Membrane Changes of Cancer Cells |
I moved to Princeton in 1961 to become the first Chairman of
the Biochemical Sciences Department. Techniques by this time had
progressed sufficiently to make tissue culture of mammalian cells
feasible for investigators in general. In 1963 an opportunity to
participate in a cancer meeting in South America reinitiated my
thinking about cancer. I needed a topic and so speculated that cancer
and normal cells differ in surface functions that regulate growth by
interacting with the extracellular environment (25). However, little
was then known about growth factors, as supplied in serum, or of their
receptors, so I turned to a surface-related activity that I had
investigated in relation to -galactosidase induction, transport of
small molecules across the membrane into E. coli. These
experiments had provided a valuable lesson. Monod and Jacob proposed
the operon model: that adjacent genes, in particular for
-galactosidase and galactoside transport (permease), are co-induced
by galactosides. I objected that the galactinol induces the transport
system but not the enzyme. The solution to this dilemma is that this
sugar is an  -galactoside, which induces a different permease that
tests positive in the assay for -galactoside permease, and so the
operon hypothesis was not contradicted (26).
Molecular mechanisms of transport were then unknown. To learn about
them, Jacques Dreyfuss and I investigated sulfate ion uptake (27) and
identified a novel class of transport-related proteins. A mutant of
Salmonella typhimurium that could not grow on sulfate did
not accumulate the ion and so was defective in its transport, but we
noted that a very small amount of sulfate was associated with these
bacteria. We hypothesized that this sulfate is bound to a protein
located outside the cell membrane, and our experiments demonstrated a
small protein located between cell wall and membrane to which sulfate
binds firmly. Its synthesis is repressed by sulfate, so by derepression
in cells grown with an organic sulfur source and followed by a
selective release technique we were able to obtain crystals after only
4-fold purification,. This sulfate binding protein is one of the first
transport proteins to be purified and the first of the "binding
proteins" that are involved in active transport and chemotaxis
(28).
We then turned to investigating transport into normal and cancer cells.
In a series of studies we showed that their transport of small
molecules differs and is highly regulated, being altered by viral
transformation, cell-cell contact, and serum addition, and it changes
through the cell cycle (29). At this time Max Burger and Allan Goldberg
joined my laboratory and investigated carbohydrate differences on
cancer versus normal cell surfaces (30), and Dennis
Cunningham investigated phospholipid turnover (31). To begin studies of
growth regulation by externally supplied growth factors we compared
their requirements by normal and transformed cells (32).
| |
Disregulation of the Cell Cycle in Cancer |
In 1972-1973 my late wife Ruth Sager and I took a sabbatical
with Sir Michael Stoker at the Imperial Cancer Research Fund Laboratory
in London. Our objectives were to learn about cancer, especially
applications of tissue culture. We worked long hours, surprising our
colleagues by sometimes returning to the laboratory after dinner; to
make up for this, we made several exciting and informative trips around Europe.
I soon decided that the hallmark of cancer on which I should focus was
deregulated cell proliferation, and Ruth chose genetic defects for her
subject of investigation, an area in which she later made major
contributions. The process of cell proliferation is organized as the
cell cycle, which provided a good starting point for me because I
previously studied cell cycle events in synchronized bacteria (33, 34).
My initial question was where in the cycle growth regulation is
exerted. I discovered that regulation for normal cells is exerted in
late G1 phase, at about 2 h prior to initiation of DNA
synthesis. This is in contrast to prior proposals that growth control
is exerted prior to cell division. Thus, a wholly different set of
molecular events came into consideration, molecules involved in which
were soon identified. I named the time of this process the restriction
point, a term that survives today (35). Lee Hartwell at this time
applied his cycle-regulating yeast mutants to demonstrate that growth
of yeast is similarly regulated in G1 at "start." The
restriction point and start are the first demonstrations of what
Hartwell later named "checkpoints."
Importantly, I showed that these restriction point requirements are
relaxed in cancer cells, providing a basis for the greater proliferative capacity of cancer (36). This research on restriction point control and its relevance to cancer have been summarized (37). We
proceeded to investigate related molecular events in G1.
Expression of the oncogenic protein Myc was changed in cancer cells
(38); we showed that transit through G1 is influenced by
serum supply, growth factors, and nutrients, and actin and other
proteins are synthesized sequentially after cells enter the cycle (39).
Rapid protein synthesis was needed to enter S phase, especially by
normal as compared with cancer cells, which suggests the requirement
for growth control of a protein with a short half-life. Indeed, we
discovered only one protein (p68) of many detected as a spot on
two-dimensional gels that had the three required characteristics. It
increased in G1, was unstable, and more was present in
cancer cells (40). Henry Yang and I demonstrated one of the first
changes of protein phosphorylation during G1, which
differed between normal and transformed cells (41).
Ruth and I moved to the Dana-Farber Cancer Institute and Harvard in
1975. I investigated the then unknown post-restriction point events at
the end of G1 that initiate onset of DNA synthesis. My
laboratory developed the appearance at the end of G1 of
thymidine kinase as an alternative marker for S phase initiation, one
that is more subject to molecular investigation than is DNA synthesis (42). Prem Reddy and I showed that several enzymes involved in DNA
synthesis are produced at the G1/S interface and
translocate into the nucleus where they form a "replitase"
multiprotein complex for DNA synthesis (17). It contains E2F,
retinoblastoma-like protein, and Cdc2 kinase. It binds to the mouse
thymidine kinase gene promoter (43). With the discovery of
cycle-dependent kinases (Cdks) and cyclins (providing
another example of interacting catalytic and regulatory proteins) we
asked whether one of these molecules is the restriction point protein.
We concluded that cyclin E is the most promising candidate (44).
Furthermore, we found that cyclin E is over expressed in cancer, and it
potentially provides a molecular marker for cancer (45).
| |
End Notes: Applications to Cancer |
By 1990 research on regulation of the cell cycle was so
plentiful and in such good hands that I decided to apply the basic knowledge I had gained to the study of cancer. On the one hand I tried
to find methods for detecting cancer earlier and on the other searched
for novel agents to treat it more effectively. This recent research
will only be touched upon here.
Gene Expression and Differential Display: Cancer
Detection--
I wanted to discover molecular changes that underlie
cancer. These could indicate mechanisms of transformation and
furthermore could provide tools for cancer detection and therapy. Peng
Liang and I invented the differential display technique for detecting the subset of mRNAs that are present in a cell and with it could discover changes in deregulated gene expressions in cancer (46). This
method is based on synthesizing short cDNAs from 3' ends of many
mRNAs and then displaying them on sequencing gels for side-by-side
comparisons of the products from normal and cancer cells. It has been
applied extensively to discover changes of gene expression; there are
now about 2000 citations of it (47). Examples from my laboratory
include discovering a gene whose expression changes downstream of
ras oncogene activity (48) and another that defectively
regulates mitosis in cancers (49).
The concept of expression genetics (also named functional genomics) has
been excellently summarized (50). Katherine Martin and Ruth Sager
systematically applied differential display to discover hundreds of
genes whose expressions are defectively regulated in breast cancers.
Their research has continued in my laboratory, demonstrating that
selected markers readily distinguished estrogen receptor positive from
negative human breast cancers and other properties (51). Then we
determined whether these markers permit cancer detection in small
samples of patient blood. We had shown that this approach is feasible
(52). Sensitivity of the assay is sufficient to detect solid tumor
cells disseminated in 3 cc of blood samples from patients (53).
Expression-based blood assays, as developed with the screening approach
described here, have the potential to detect and classify solid tumor
cells originating from virtually any primary site in the body. Earlier
detection should be effective in reducing cancer mortality, especially
as better therapies are developed.
Novel Chemotherapies--
Based on cell cycle control studies,
long ago I proposed a modification of chemotherapy based upon
protecting normal cells from drug-induced death, thereby increasing the
therapeutic index (54). This concept has recently been developed
further (55). As another checkpoint-based approach, Ching Lau and I
discovered that a caffeine derivative selectively makes DNA-damaged
cancer cells pass through their G2 checkpoint, causing
chromosome fragmentation and death (56). This effect was specific for
killing cancer cells put into mice (57). These findings led to clinical
trials, unfortunately unsuccessful because of nausea and vomiting.
We are now developing several potential anticancer therapies. A natural
product -lapachone (58) combined with taxol is remarkably effective
against tumors implanted into mice (59). We also reported anti-AIDS
effects of -lapachone and two other compounds (60). An important
novel chemotherapy is based upon specifically causing programmed cell
death (apoptosis) of cancer cells, as demonstrated with -lapachone
by Chiang Li (61). As another chemotherapeutic approach, Debajit Biswas
demonstrated that the kinase C inhibitor Go6976 specifically causes
apoptosis of estrogen receptor negative (ER ) breast cancer cells and
the disappearance of tumors from their implantation in mice (62). This
drug blocks activation of transcription factor NF- B, which is
elevated by epidermal growth factor in many ER cancers. NF-B is
anti-apoptotic, and Go6976 recreates the apoptotic capacity of these
cells, a novel demonstration of a chemotherapeutic principle.
In conclusion, my scientific path has meandered, not following any
central direct pathway, if such a pathway exists, but rather it led
along byways and across unexplored terrain toward my goal of learning
about the defects of molecular regulation that underlie cancer. My wish
is that these results will prove to be useful.
Dedicated to my late wife, Ruth Sager.
Address correspondence to:
arthur_pardee@dfci.harvard.edu.
| |
FOOTNOTES |
Published, JBC Papers in Press, June 5, 2002, DOI 10.1074/jbc.R200013200
| |
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N. Kresge, R. D. Simoni, and R. L. Hill
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[Full Text]
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