Metabolic Regulatory
Circuits and Carcinogenesis
HENRY C. PIT0T AND CHARLES HEIDELBERGER*
(McArdle
Memorial Laboratory,
The Medical School, University of Wisconsin,
Madison,
Wiscoarmn)
SUMMARY
Recent studies on the control of enzyme synthesis and activity in microorganisms
which have been carried out largely in the laboratory of Jacob and Monod in Paris
have led to the formulation of a model which in its general form agrees with much of
the known experimental data. Basically, the genetic apparatus for enzyme synthesis
is thought to consist of regulator genes which produce cytoplasmic products known as
repressors and an operon consisting of an operator and structural genes. The product
of the regulator gene together with small molecular weight, usually exogenous, regu
latons interacts with the operator gene to control the expression of the entire operon.
This basic circuit may be modified in a number of ways to produce an equally varied
number of phenotypes
Several of these phenotypes may be perpetuated by a short ex
posure of the regulator, here thought of as a carcinogen, to the system. Such a picture
fits the known concepts of chemical carcinogenesis and shows in a theoretical manner
how a malignant cell may be produced in the absence of a genetic (DNA) change. If
malignancy is not the result of a direct gene (DNA) mutation, a reversion from the
malignant to the nonmalignant state is well within reason.
The deletion theory of carcinogenesis (11,
@,
@6, @7)has been closely related to the burgeoning
efforts to develop an understanding
of the media
nisms of carcinogenesis, particularly
of chemical
carcinogenesis. The demonstration
of the binding
Of hepatocarcinogenic
aminoazo dyes to soluble
liver proteins (@1) has been followed by a consid
enable body of correlative quantitative
data that
point with a high degree of probability
to the
causal association between the processes of pro
tein binding and carcinogenesis (@) Similar find
ings have been made with acetylaminofluorene
in
rat liver (36) and carcinogenic hydrocarbons
in
mouse skin (1, 8). In these three cases there is a
quantitative
relationship between the amount of
binding of carcinogen to an electrophoretically
distinct soluble protein and the carcinogenic ac
tivity of the compound (1, @8, @9)Furthermore,
in almost all cases the protein to which the carci
nogenic compound is bound is deleted from the
tumors subsequently induced (1, @8,%9). In recent
years the molecular biologists have provided a
clearer understa@iding of the functions and inter
actions of the trinity of DNA, RNA, and protein.
C American
@
Received
Cancer
Society
for publication
Professor
of Oncology.
June 25, 1963.
As a result of this added knowledge, the evidence
for the induction of cancer as a consequence of the
binding of carcinogenic compounds to cytoplasmic
proteins has been summarily dismissed by a num
ben of authorities because they could visualize no
simple mechanism whereby the deletion resulting
from such an interaction could be perpetuated
in
subsequent generations of cancer cells.
Within the past few years there have been a
number of apparent demonstrations
of interac
tions of carcinogenic hydrocarbons
and DNA in
vitro (4, @0)'as well as in vivo (1@). Although no
evidence has yet been presented to relate such an
interaction to the carcinogenic process, the attrac
tiveness of the simple idea that a somatic mutation
to cancer may result from a direct interaction of
carcinogen with genetic material has led to its
acceptance by many as the mechanism of carcino
genesis on the basis of theoretical simplicity rather
than of scientific data.
In recent years the brilliant minds of Monod
and Jacob at the Pasteur Institute in Paris have
1 Note
added
in
proof:
It
has
now
been
shown
(B.
P.
Giovanella, L. E. McKlnney, and C. Heidelberger, J. Mol.
BiOZ. [in press])
20) purporting
hydrocarbons
that the interpretations
of the experiments
(4,
to demonstrate
in vitro interactions
between
and DNA were fallacious.
.
1694
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PITOT AND HEIDELBERGER—RegUZatOr-JJ Circuits
provided a number of ideas that explain in a uni
fled fashion the genetics and regulation of cellular
activity in microorganisms
(15). More recently,
they have proposed the concept of “allostericin
hibition― and have brilliantly extended this to
the construction
of theoretical control circuitry
that is capable of explaining many facets of the
regulation of systems as complex as those of mam
ma!ian differentiation
(17, @3).In the present
paper we wish to point out that, by suitable appli
cation of their theories, it is possible to explain
how a cytoplasmic interaction of a carcinogen and
a target protein could lead to a permanently
al
tered and stable metabolic situation without the
necessity of any direct interaction of the carcino
gen and genetic material. It is furthermore a con
sequence of this theory that, under the proper
circumstances and before chromosomal alterations
occurred, the process might be reversed and lead
to the production of a normal from a tumor cell.
ELEMENTS
OF ENZYME
REGULATION
It is now clear from the work of Jacob and
Monod (15), Yates and Pardee (37), Umbarger
(31), Changeux (6), and others that the regulation
of enzymatic function occurs at both the genetic
and enzymic level. The former process occurs .by
alteration of the rate of synthesis of the enzyme;
®I
REGULATOR
MOLECULE
CHART 1.—Enzyme subject to allosteric inhibition
the latter through specific effects of small molec
ular components on the activity of the enzyme.
From these studies new concepts of biochemistry
have emerged which in turn require new terms to
facilitate discussion and understanding.
Some of
@ these terms are here defined:
Induction: an increase in the rate of the syn
thesis of an enzyme(s) brought about by the addi
tion to the environment
of a specific small mo
lecular component(s),
usually the substrate of the
enzyme induced. Enzyme induction, in general, is
found to involve enzymes of catabolic pathways.
Repression: a cessation or marked reduction in
the rate of the synthesis of an enzyme(s) resulting
from the addition to the environment of a specific
small molecular component(s),
usually the final
product of the biosynthetic
pathway involved.
Repression, in general, is associated with pathways
and Cardnogenesi@
1695
involving the biosynthesis of essential metabolites
—e.g., amino acids, punines, pynimidines, etc.
Feedback inhibition: inhibition of the activity of
the initial enzyme of a biosynthetic
sequence by
the final product of the sequence. In general,
feedback inhibitors also act to repress the syn
thesis of all the enzymes in the biosynthetic path
way.
ENZYME
REGULATION
AT THE ENZYMATIC
LEVEL
As defined above, some systems are regulated
by final-product
inhibition of the initial enzyme
in the sequence. Such a process is somewhat analo
gous to the feedback ioops seen in electronic cir
cuitry. In biological systems, however, the circuit
connection appears to reside in a specific regula
tory site on the enzyme which is distinct from,
®
1SUBSTRAT@j
CHART 2.—Enzyme inhibited
allosterically
but which interacts with, the catalytic site (6).
Such inhibition has been termed “allostericinhibi
tion―and has been more explicitly defined (17, %3)
Diagrammatically
the enzyme might appear as in
Chart 1. Here the enzyme is seen as a box with a
regulator site (semicircle)-.on one side and a slot
for the catalytic site on the other side. The regu
lator molecule (inhibitor or activator as the case
may be) fits specifically into the regulator site
much as a substrate would do on the catalytic
site. However, the regulator, when present, affects
the enzyme—perhaps its conformation—in such a
way as to produce an inhibition of the activity of
the catalytic site. This might be imagined, for ex
ample, as an overlapping or interference of the
two sites brought about by contact with the in
hibitor resulting in an alteration of the configura
tion of the catalytic site. This is diagramed in
Chart
By suitable manipulation
of the enzyme, such
as gentle heating,
treatment
with sulfhydryl
(SH) inhibitors, etc., this model suggests that the
inhibitory
site could be selectively inactivated
without interfering with the catalytic site. Such,
in fact, has been found to be the case with cytidine
triphosphate inhibition of aspartic transcarbamy!
a.se (10) and the isoleucine inhibition of threonine
deaminase (6). Furthermore,
studies have shown
that the capacity for allosteric inhibition of an
enzyme may be lost during purification.
In at
least one case, loss of allosteric inhibition is accom
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@‘
@)
Cancer Research
1696
Vol.
@3,November
1963
panied by a change in the sedimentation
constant
of the enzyme (@5), further evidence in favor of
the importance of the conformation of the protein
in this specific type of inhibition.
@
plementary
strand of RNA, termed messenger
RNA (m-RNA) and possessing the information
coded in the gene. This metabolically
active m
RNA then attaches to several nibosomes forming a
nibosomal-m-RNA
aggregate
(polysome)
which
Er@zmz REGULATION AT THE Gz@TIc LEVEL
serves as a template for amino acid-soluble RNA
Probably more important for the over-all cellu
complexes (34). The latter complexes attach to
lar economy is the regulation of enzyme synthesis
the polysome in the sequence ordered by the
brought about by small molecular metabolites in m-RNA, peptide-bonds
are formed, and the pro
the environment. The terms induction and repres
tein is released from the template (35). This com
sion have previously been defined with reference
plex is shown diagrammatically
in Chart 3 by a
to this subject. It is in the current concepts of the
series of three short arrows between the m-RNA
mechanism of these two processes that we are in
and the enzyme. The regulator gene is envisaged
terested.
as producing its own m-RNA, which in turn pro
Through the careful and imaginative study of grams the synthesis of an endogenous repressor,
a host of microbial mutants with respect to en
active in the induction system (Chart SA) but in
active in the repression system (SB). This, too,
A) PIOUC11ON
OP@l
may be a protein which in the proper configuration
1@@JL..qvR
GE?Ll@
5@TWJCTURAL.
GE?Lt
could react with the m-RNA of the 0 gene effec
-+@
w@m-RNA
tively, thus blocking further synthesis of m-RNA
in the entire operon. Although the exact nature
of the endogenous repressor is not known, the
extreme degree of specificity exhibited by the exog
enous regulator (small molecular metabolite)
in
M0I@E@:::
S [email protected]
REP@53OR
the process, as well as the temperature
effed on
@M'4L
the regulation of enzyme synthesis (13), makes it
B) [email protected]@0N
likely
that the endogenous regulator, the repres
@L@OR
@l
I
@WL
son, is protein or at least part protein in its struc
tune. In fact, it has been suggested (17) that the
repressor protein in biosynthetic pathways has an
active site which may resemble the regulator site
responsible for allosteric inhibition (negative feed
back) at the enzymatic level. Such a model is
R
portrayed
in Chart 3. An allosteric endogenous
regulator would reduce the number of variables
Cuawr 3.—Basic regulatory circuit. See text for explana
required in the already highly complex biological
tion of general scheme.
system. It can also account for the high degree of
specificity exhibited by the product of the regu
zymes exhibiting inductive and/or repressive reg
lator gene for the exogenous regulator.
ulation, the Paris group, especially Jacob and
This basic regulatory
circuit can be used to
Monod, have advanced an hypothesis to explain
explain both enzyme induction and repression. In
the mechanisms involved in the regulation of en
the former case (Chart BA), the product of the
zyme synthesis in living cells (15). The basic
regulator gene, termed the repressor, interacts at
concept can best be portrayed by the models seen
the 0 gene to prevent the synthesis of the struc
in Chart 32 Here the chromosomal DNA is repre
tunal gene products. S, an inducer, may combine
sented by the double line. On the left, separated
with and inactivate the repressor, thus allowing
from the functional unit, is the regulator gene.
enzyme synthesis—i.e., enzyme induction. Con
‘Onthe right is the unit, termed the operon (17),
versely, in a repressible system (Chart SB) the
-which consists of an 0 or operator gene and one
product of the regulator gene is inactive by itself
-or more structural genes, the latter possessing the
and is termed an aporepressor.
The exogenous
structural information for the enzyme protein. The
regulator,
R, combines with the endogenously
gene acts as a template for the synthesis of a com
formed aporepresson to give an active repressor,
Ifi the reader is interested in the detailed theoretical basis which now shuts off enzyme synthesis by inter
for the regulatory circuits outlined here, he is referred to the action at 0—hence, enzyme repression.
more comprehensive papers (15—17)dealing with this subject
The unit, operator gene plus structural
gene,
Such considerations,
requiring
considerable
background
in
has been termed the operon and may consist of
microbial genetics, are not within the scope of this manuscript
t@F]
@
@
@
_
@t @r_tRNA
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PIT0T AND HEIDELBERGER—RegUlatOry
@
@
many structural genes, although they are usually
interrelated
in some way as to their function
i.e., function in a single biosynthetic pathway. The
products of the regulator gene and the environ
ment thus alter the expression of the operon as a
unit by interaction
at the operator gene of the
operon. In addition to mutations
in structural
genes leading to changes in amino acid sequence in
enzymes, mutations may occur in the regulator or
the 0 gene leading to changes in the regulation of
enzyme synthesis. A mutation
in the regulator
gene may result in a defective repressor incapable
of interacting with 0. Thus enzyme synthesis pro
ceeds irrespective of R, or the repressor. This is
known
as constituitive
enzyme
synthesis.
Also,
as a result of mutation, the repressor may become
incapable of combining with R and result in max
imum synthesis of a repressible enzyme or abso
lutely no synthesis of an inducible enzyme. Simi
larly, mutations
in 0 can result in a failure of
interaction with the repressor, also giving rise to
constituitivity.
A more detailed discussion of the
many effects of mutations
in the operator and
regulator genes may be found elsewhere (15, 16).
It should be re-emphasized that Chart 3 represents
the model of Jacob and Monod and is not original
with the present authors.
REGULATORY
CIRCUITS
IN MULTI
CELLULAR
ORGANISMS
The systems and control circuits outlined thus
far have been worked out primarily in bacteria.
However, there is reason to believe that essentially
similar control circuits exist in mammals, although
the complexity is much greater, and thus the con
trol systems would be expected to be more intni
cate (@4). For example, the maintenance
of the
milieu intérieur of the mammal, which is largely
regulated by the interplay of the endocrines, de
pends on physiologic interactions programed much
like the regulatory circuits discussed here (9). The
existence of inducible (19) and repressible (33)
mammalian enzymes points to basic similarities in
the control of enzymatic synthesis in uni- and
multicellular organisms. Recent studies have also
indicated that feedback inhibition at the enzy
matic level may also exist in the mammal (5, 14).
It should be pointed out, however, that consid
eration of the basic control circuit in Chart 3 as
an inflexible unit such as seen in @-galactosidase
induction in E. coli would be an oversimplification
where multicellular organisms are concerned. For
example, S or R may be seemingly unrelated func
tionally to the enzyme products of the structural
gene it co-regulates with the regulator gene prod
uct. Thus, a substrate—e.g., drug, toxin, metabo
Circuits
and Cardnogenesi@
1697
lite, etc.—may induce enzymes seemingly unrelated
to its metabolism—e.g.,
cortisone induction
of
tyrosine transaminase
(18). Similarly, a distal
product may repress and exhibit negative feedback
or allosteric inhibition on the initial enzyme of a
seemingly unrelated sequence as outlined in Chart
4. Product Z of sequence
may repress and exhibit
negative feedback on enzyme 1 of sequence 1. Such
a phenomenon has been termed cross-feedback (@4).
Similarly, the two sequences could be cross-linked
so that the product E repressed the synthesis of
enzyme a of sequence
@.Operationally,
when se
quence 1 is operating sequence
will be repressed
and vice versa. Monod and Jacob have outlined
such circuits (@4), and at least one possible exam
ple of this type has been found in the mammal (3).
REGULATORY
CIRCUITS
AND
CARCINOGENESIS
Since it appears clear that the prime biologic
(and therefore biochemical) defect in the malig
nant cell resides in the regulation and control of
cell function and growth, the concepts outlined
here take on an added importance with respect to
malignancy. However, the theoretical model is of
little use unless it can ultimately
be tested on
applied. Thus, in furtherance of our objective, we
wish to demonstrate how the theory of regulatory
circuits can be used to suggest explanations
and
experiments in the field of carcinogenesis.
“Cytoplasmic―
inheritance.—The entire question
of a “self-sustaining―or “self-reproducing―cyto
plasmic unit has long intrigued biologists and bio
chemists.
Certain authors have suggested the
existence of such units from experimental data (7,
30, 3@), and the term “plasmagene―
has been used
by some with respect to cytoplasmic inheritance.
It is also of interest that virtually identical pheno
types may be obtained in bacteria following pri
mary events which are either genetic or genotypic
Thus, the genetic or nongenetic nature of some
primary event cannot be determined exclusively
by consideration of the nature or of the degree of
stability of the biochemical phenotype.3
By a slight manipulation
of the basic circuit of
Chart 3, it is possible to have a control circuit
which acts as a self-sustaining
unit. This is seen
in Chart 5.
Here, the product R of the reaction catalyzed
by enzyme E, or a sequence of E's produced by
the operon, is the inducer of E. Thus, as long as
any substrate S is available, the enzyme level is
maintained,
since the product R which is formed
interacts with the repressor formed by the regu
lator gene so as to inactivate it—hence, enzyme
I
Personal
communication,
Prof.
J.
Monod.
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@
@L
Cancer Research
1698
synthesis persists. However, when no more S is
available, enzyme synthesis stops and the system
is nonfunctionaL
This system has been further
discussed by Monod and Jacob (@4).
Although such a circuit can be used to explain
some apparent self-sustaining
cytoplasmic units,
it cannot readily be used as a model for chemical
carcinogenesis, particularly in a two-stage mecha
nism (s), wherein the carcinogen acts for only a
limited time period but gives rise to apparent
I
2
3
A—.B@C---IPD—.E
@
4
r
@
SEQUENCE I
@
letters represent metabolites,
represent enzymes in each
metabolite
of each sequence
repression of the first enzyme
and numbers and Greek letters
sequence. The final product or
causes allosteric inhibition and
in the alternatesequence.
Such
a scheme
to include
could
@j
Vol.
@3,November
1963
of which limits growth in cells, then one can en
visage a perpetuated growth of cells with E present
in considerable amounts.5 The product of E—i.e.,
R, will be present in dividing cells as well as their
daughter cells because of sharing of the cytoplasm
resulting in an “inherited―repression of RG2.
Thus, according to this model, the protein to
which the carcinogen is bound is the repressor of
this growth process; this repressor is deleted in the
cancer cells, and this deletion does not depend on
the continued
presence of the carcinogen
in
daughter cells.
Slight modifications of this circuit could give
rise to the same thing—e.g., have the carcinogen
act as an exogenous repressor with the product of
SEQUENCE2 RG@but allow the rest of the circuit to remain the
Cuaa'r 4.—Cross repression and/or feedback. Capital
@
@_/
be extended
many
same. It is also possible, as shown by Monod and
Jacob (@@4),to envisage a circuit in which the
i@at°d
I
@Q
4@J 51WJCPJRALGEPLI
‘7@@
\
t@__,-@__:@;
e
@]
@.‘.
@Tf@1
sequences.
@-
l@UL@TCRGEPiEI
I
—%-@‘@@-—
_l_@J
sTnJc-TuR@
GE@Et
t
[c@@Iw45cTNEI
Cl:
CHART6.—Modifiedproduct perpetuation circuit. See text
Ti®
for explanation of this scheme. Carcin —carcinogen which
combines with and inactivates the product of RO, which in
turn allows synthesis of E, maintaining
RG2 in the inactive
state. Note that the carcinogen need act for only a short
period of time until sufficient E is synthesized to completely
@
Ciwrr 5.—Basic product perpetuation
circuit. The regu
latory gene produces an active endogenous repressor which
prevents synthesis of E. Addition of 14 the product of the
reaction catalyzed by E, allows synthesis of E as long as S
is present.
hereditary
change. However, by another slight
modification of the basic circuit one may deduce
a theoretical model to fit the above requirements
of carcinogenesis. This is seen in Chart 6. In this
modification the active repressor product of 1W2
normally prevents any synthesis of E via the
structural gene.4 However, carcinogenic chemicals
may bind with the RG2 repressor to inactivate it.
Noncarcinogens
may bind but not inactivate, or
may bind to proteins other than the product of
JIG2.Once the repressor is inactivated E is synthe
sized, and the essential metabolite
8, which is
assumed always to be available, is converted to
R which now acts as an exogenous repressor in
conjunction with the product of RG5 to inactivate
operon-@, thus allowing perpetual synthesis of E.
If E is considered to be an enzyme(s) the absence
4 It is obvious
turnover
that
number, butthe
some
E may
be
over-alleffects
formed
if E has
a low
would not be changed.
repress synthesis
of the RO, product
L@j
@JCTUR@
GENERGzt
__________________
loll RGII
1@P@TNE]
®J-®
Ca&wr
7.—Product
independent
circuit.
See text
and
legend of Chart 6 for explanation. Note that this differs from
the circuit of Chart 6 in that R does not enter into the regu
latory
circuit.
product of the structural gene does not
the control system as seen in Chart
system, as long as no carcinogen—i.e.,
inducer—is present, the products of the
enter into
7. In this
exogenous
structural
a A similar model can be used to describe the mechanism of
liver regeneration or any non-neoplastic
cellular proliferation.
However, here the model must be capable of reversion to its
original state. Such will be the case if the organism itself re
places the product of 1W,, thus reverting the system to its
original state. That a similar thing is possible in neoplasia is
discussed further. Another explanation of self-limiting non
neoplastic cellular proliferation
entirely different circuits.
is that they are regulated
by
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PITOT AND HEIDELBERGER—RegULatOrIJ
gene, SG, are not synthesized. If, however, a car
cinogen inactivates the repressor produced by RG1,
then 02 @S
unlocked and SO and RG2 are formed
and act to prevent any further synthesis of ne
pressor by the regulator gene, RG1, whose activity
is controlled by Oi. Thus enzyme synthesis from
SG is perpetuated.
However, an inducer macti
vating the product of RG2 even for a short time
would convert the system back to its original in
active state. Similarly, it could be argued that, in
Chart 6, if the product of RG2 could be replaced
in the system for a sufficient period of time to
eliminate E, the system would revert to its original
inactive state. Also, in the system in Chart 6, if
it would ever be possible to starve the cell of S
completely for a sufficient time to eliminate E,
RG2 would again become active and the system
returned to its original state. Here it might also
be noted that mammalian
systems would differ
from bacterial in that the former exhibit enzyme
turnover and thus have a means of eliminating the
enzyme formed after its synthesis is stopped. A
more practical method might be to inhibit E in
order to get the same effect. All these possibilities
would result in reverting the altered or “malig
nant― state back to the original or “normal.―
Such
concepts are not unheard of in cancer research, and
they suggest new fields to be investigated in our
attempts to control the disease. If malignancy is
not the result of a direct gene (DNA) mutation, a
reversion from the malignant to the nonmalignant
state is well within reason.
It must be apparent to the reader that we are
here dealing only with the earliest changes in
carcinogenesis.
Once the altered regulation is es
tablished (possibly within minutes on hours), other
effects appear, such as aneuploidy, increased glycol
ysis, apparent
multiple enzyme deletions, etc.,
which are probably secondary to the primary
change.
It is not our intention to rule out or deny the
possibility that chemical carcinogenesis is a con
sequence of the direct interaction of the compound
with genetic material. Rather, it is our purpose to
call attention
to alternative
explanations,
based
upon present concepts of metabolic regulation and
control, that permit the perpetuation
of metabolic
changes brought about by the temporary
inter
action of the carcinogen and a cytoplasmic protein.
Thus, by the application of these or similar theo
retical models it is possible to reconcile the large
body of sound experimental data on chemical car
cinogenesis with present concepts of metabolic
regulation, and early cancer could be considered as
a phenotypic rather than a genotypic disease.
Circuits
1699
and Carcinogenesis
ACKNOWLEDGMENTS
We acknowledgewith gratitude ProfessorJacques Monod's
interest
in and review of this manuscript.
We also are grateful
to our colleaguesin the McArdle Memorial Laboratory of the
University
of Wisconsin
for their helpful suggestions.
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Metabolic Regulatory Circuits and Carcinogenesis
Henry C. Pitot and Charles Heidelberger
Cancer Res 1963;23:1694-1700.
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