Pergamon

PII: S1357-2725(97)00085-X 1357.27x97 517 00 0 00

INTRODUCTORY OVERVIEW
Transcription Factors: An Overview
DAVID S. LATCHMAN
Deppcrrtment of Molecular Pathology, Windeyer Institute I$ Medical Sciences, University College
London Medical School, The Windeyer Building, 46 Cleveland Street, London WIP 6DB, C’.K.

This special issue of the International Journal of Biochemistry and Cell Biology contains a
series of review articles and original papers dealing with the topic of transcription factors. The
purpose of this introductory article is to provide an overview of these factors, their mechanism
of action, their regulation and the manner in which alterations in them can result in disease.
‘<‘: 1997 Elsevier Science Ltd. All rights reserved
Keywords: Transcription factors Gene regulation
Int. J. Biochem. Crll Biol. (1997) 29, 1305-1312

TRANSCRIPTIONAL CONTROL genes which do not show this pattern of in-

duction.
The regulation of gene transcription is central
The proof that such sequences are of critical
both to tissue specific-gene expression and to
importance in producing the pattern of gene
the regulation of gene activity in response to
transcription was provided in the case of the
specific stimuli (for review, see Latchman,
HSE by the experiments of Pelham (1982).
1995a). Thus, whilst some cases of regulation who transferred the heat shock element from
after transcription do exist, in most cases regu- the heat inducible hsp70 gene onto the non-
lation occurs at the level of transcription by heat inducible thymidine kinase gene. When
deciding which genes will be transcribed into this hybrid gene was introduced into cells and
the primary RNA transcript. Once this has the temperature subsequently raised, increased
occurred, the remaining stages of gene ex- thymidine kinase production was detected in-
pression, such as RNA splicing, occur auto- dicating that the HSE can direct heat inducible
matically and result in the production of the transcription of a gene which is not normally
corresponding protein. inducible in this manner. Subsequent studies
Inspection of the regulatory regions of genes have produced similar results with other such
which showed similar patterns of transcrip- regulatory elements such as the GRE or the
tion, revealed the presence of short DNA cyclic AMP response element (CRE) (for
sequences which were held in common by review, see Latchman, 1995a).
genes with a particular pattern of regulation It is now clear that these short DNA
but were absent from other genes which did sequences act by binding specific regulatory
not show this pattern of regulation. Thus, for proteins known as transcription factors, which
example, genes whose transcription is induced in turn regulate the transcription of the gene
in response to exposure to elevated tempera- either positively or negatively so as to produce
the observed effect on transcription (for
ture contain a common regulatory element
review, see Latchman, 1995b).
known as the heat shock element (HSE),
which is absent from genes that do not show
heat inducible transcription (Davidson et al., MECHANISM OF ACTION OF TRANSCRWTION
FACTORS
1983). Similarly, genes whose transcription is
induced by exposure to glucocorticoid hor- In order to produce their effects, transcrip-
mone contain a common glucocorticoid re- tion factors will, in general, require the ability
sponse element (GRE), which is absent in to bind to DNA and then to influence tran-
1305
1306 David S. Latchman

(a) GCN4

N
1

Transmptional DNA
actwation bndlng

(b) Glucococticoid receptor

421 526
1 200 400 486558 777

Trawdptbnal
activation activatii

Fig. 1. Structure of the yeast GCN-4 factor: (a) and the mammalian glucocorticoid receptor; (b) indi-
cating the distinct regions that mediate DNA binding or transcription activation.

scription either positively or negatively. Each scription factors (for review, see Kornberg,
of these aspects will be considered in turn. 1993); the two cysteine-two histidine zinc fin-
ger (for review, see Rhodes and Klug, 1993)
DNA binding which is found, for example, in the Sp tran-
Detailed analysis of a number of different scription factor family (see Lania et al., this
transcription factors has indicated that they issue); the multi-cysteine zinc finger (for
have a modular structure in which specific review, see Parker, 1993) which is found in the
regions of the molecule are responsible for steroid-thyroid hormone receptor family (see
binding to the DNA, whilst other regions pro- Grandien et al. and Tenbaum and
duce a stimulatory or inhibitory effect on tran- Baniahamad, this issue); the Ets domain (see
scription (Fig. 1). Studies on the DNA Sharrocks et al., this issue); and the basic
binding regions of different transcription fac- DNA binding domain.
tors have revealed several distinct structural el- This last example is of particular interest
ements which can produce DNA binding (for since factors containing the basic DNA bind-
reviews, see Harrison, 1991; Travers, 1993). ing domain can only bind to DNA once they
Indeed transcription factors are frequently have formed transcription factor dimers.
classified on the basis of their DNA binding Hence, factors containing the basic binding
domains and a selection of these binding domain are further sub-grouped according to
domains is listed in Table 1. Well character- the nature of the dimerization motif which
ized DNA binding domains include: the helix- they contain. Thus, some of these factors such
turn-helix motif found in the homeobox tran- as the transcription factors discussed in the

Table 1. Transcription factor families classified by their DNA binding domains

Domain Factors containing domain Comments

Homeobox Numerous Drosophila homeotic genes, DNA binding mediated via helix-turn-helix
related genes in other organisms motif
POU Ott-1, Ott-2, Pit-l, Uric-86 Consists of POU-specific domain and POU-
homeobox
Paired box Various Drosphila segmentation genes, Often found together with a homeobox in
PAX factors PAX factors
Cysteine-histidine zinc finger TFIIIA, Kruppel, SPl, etc. Multiple copies of finger motif
Cysteine-cysteine zinc finger Steroid-thyroid hormone receptor family Single pairs of fingers, related motifs in
Adenovirus ElA and yeast GAL4, etc.
Basic element C/EBP, c-fos, c-jun, GCN4 Often found in association with leucine zipper
or helix-loopphelix dimerization motifs
Ets domain Ets-1, Elk-l, SAP Contain helix-turn-helix motif
 Transcription factors: an overview lW7

article by Kageyama et al. (this issue), contain

a helix-loop-helix motif which mediates
dimerization (for review, see Littlewood and
ABS TATA +l
Evan, 1995). In contrast, other basic DNA
binding domain-containing factors such as the
CREB factor discussed by Sassone-Corsi (this Stlmulatlon of complex assembly

issue), undergo dimerization via the so-called

leucine zipper motif which contains a regular
array of leucine residues (for reviews, see
Hurst, 1996; Kerppola and Curran, 1995).
Thus, a wide variety of DNA binding
domains (which in some cases have associated
dimerization domains) allow transcription fac-
ABS TATA +l
tors to bind to their appropriate DNA
sequences within target genes. It is now necess-
ary to consider how the transcription factors
are able to influence the rate of transcription
following such DNA binding.
I Shmuiation of complex actrvrty

Activation of transcription
As illustrated in Fig. 1, many transcription
factors contain, in addition to the DNA bind-
ing domain, specific regions which are necess-
ary for the activation of transcription. Such ABS TATA +l

regions were identified on the basis that they

can stimulate transcription when linked to the Fig. 2. An activator (A) bound to its binding site (ABS)
DNA binding domain of a completely unre- can stimulate either the assembly of the basal transcrip-
tional complex consisting of RNA polymerase and its as-
lated factor and are known as activation
sociated factors, or stimulate its activity once it has
domains (for review, see Mitchell and Tjian, assembled.
1989). As with DNA binding domains, a num-
ber of distinct types of activation domain have specific activating transcription factors can
been identified which are defined on the basis interact with the basal transcriptional complex
that they are rich in acidic amino acids, gluta- so as to stimulate transcription. In this man-
mine residues or proline residues, respectively. ner, the binding of specific transcription fac-
These activation domains appear to function tors can stimulate gene transcription.
by interacting with components of the basal
transcriptional complex. This is a complex of
RNA polymerase II and various transcription Repression of transcription
factors such as TFIIB and TFIID which Although it was originally thought that
assembles at the gene promoter and is essential most eukaryotic transcription factors acted by
for transcription to occur (Fig. 2) (for review, stimulating transcription, it has now become
see Roeder, 1996; Nikolev and Burley, 1997). clear that a wide variety of factors act by inhi-
Activation domains have been shown to inter- biting the transcription of specific genes and
act either directly with specific components of that such inhibitory transcription factors may
this complex, or indirectly by interacting with be at least as important as stimulatory factors
so called co-activator molecules which then (for review, see Herschbach and Johnson,
interact with the basal complex itself. 1993; Hanna-Rose and Hansen, 1996:
Whatever the case, such interactions appear to Latchman, 1996b).
result in enhanced transcription either by sti- The earliest examples of such inhibitory
mulating the rate of transcription factor com- transcription factors were shown to act by
plex assembly, or by stimulating the level of interfering with the activity of a positively act-
its activity (see Fig. 2). ing factor, thereby blocking its stimulatory
Hence, following binding to their appropri- effect on transcription (Fig. 3aac). This could
ate DNA binding site mediated via the DNA be achieved, for example, by preventing the
binding domain, the activation domains of positively acting factor from binding to DNA
130x David S. Latchman

(a)

Gene a&e Gene inactive

(b)

GetTG&e Gene Inactive

(C)

(d)

@7 Directrefxesim
GHR?active Gene inactive

Fig. 3. Potential mechanisms by which a transcription factor can repress gene expression. This can
occur; (a) by the repressor (R) binding to DNA and preventing an activator (A) from binding and acti-
vating gene expression; (b) by the repressor interacting with the activator in solution and preventing its
DNA binding; (c) by the repressor binding to DNA with the activator and neutralizing its abiltiy to
activate gene expression; or (d) by direct repression by an inhibitory transcription factor.

either via the negatively acting factor binding repressors to the regulatory region of a par-
to its DNA binding site (Fig. 3a), or by the ticular gene will determine the rate of its tran-
formation of a non-DNA binding protein- scription in any particular situation. Clearly,
protein complex between the positively acting however, in order for a particular gene to
factor and the negatively acting factor respond to specific signals or to be regulated
(Fig. 3b). Alternatively, the negatively acting in a cell type specific manner, the balance
factor could act by interacting with the posi- between these activating and repressing mol-
tively acting factor to block the activity of its ecules must change in different situations. The
activation domain in a phenomenon known as mechanisms which are used to regulate tran-
quenching (Fig. 3~). scription factor activity are discussed in the
It has now become clear, however, that a next section.
class of inhibitory transcription factors exists
which can directly inhibit transcription even in
the absence of a positively acting factor REGULATION OF TRANSCRIPTION FACTORS
(Fig. 3 d). These factors can thus reduce the Transcription factors can be regulated at
basal level of transcription below that two levels, namely the regulation of transcrip-
observed even in the absence of any activating tion factor synthesis and the regulation of
molecule and appear to function by interacting transcription factor activity (Fig. 4).
either directly or indirectly with the basal tran-
scriptional complex so as to reduce its activity. Regulation of synthesis
They thus constitute the antithesis of the acti- In a number of different situations, a tran-
vating molecules discussed in the previous sec- scription factor is regulated by being syn-
tion and possess defined inhibitory domains thesized in one particular tissue or cell type
which are responsible for their effects and and not in other tissues. The most dramatic
which, like activation domains, can function example of this concerns the MyoD transcrip-
when transferred to the DNA binding domain tion factor which is synthesized only in skel-
of another molecule (for review, see etal muscle cells. Thus, in this case, the over-
Latchman, 1996b). expression of the MyoD factor in undifferen-
Hence, the balance between binding of tran- tiated fibroblast cells is sufficient to convert
scriptional activators and transcriptional them to skeletal muscle cells indicating the
 Transcription factors: an overview I :w9

(a) exposure to IL-6 (Ramji et al., 1993) as dis-

Tissue 1 Tissue 2 cussed in the article by Akira et al. (this issue).

Factor
Regulation of transcription ,factor activit)
No factor present Although the regulation of transcription fac-
-FL
tor synthesis is an important control point, it
Gene wztive GGiZVe
cannot be the only regulatory mechanism
which controls transcription factor activity.
Thus, if this was the case, the enhanced syn-
thesis of a transcription factor in response to a
(b)
l-s.sue 1 Tissue2 particular stimulus would be controlled by
enhanced transcription of its corresponding
Factor Factor gene, which in turn would require the de now
inactive cl activated synthesis of further transcription factors, so
resulting in the need for new transcription of
Gene inactive Gene active these genes and so on.
Fig. 4. Gene activation mediated by the synthesis of a
Therefore, it is necessary to have an ad-
transcription factor only in a specific tissue (a), or its acti- ditional mechanism which allows de wove gene
vation in a specific tissue (b). transcription by the activation of pre-existing
transcription factors (Fig. 4b). Indeed, even in
the case of IL-6, as discussed by Akira (this
critical role for this factor in the induction of issue), the enhanced synthesis of the transcrip-
muscle specific gene expression (for review, see tion factor NF-IL6/3 induced by IL-6, is comple-
Edmondson and Olson, 1993). mented by the activation of other transcription
Although regulation of synthesis is primarily factors, NF IL-6 and STAT-3 which pre-exist in
used to regulate transcription factors which inactive form in unstimulated cells
control cell type or tissue specific gene ex- .?tutticken et al., 1994; Nakajima et al., 1993).
pression, it can also be used to regulate tran- Such activation of pre-existing transcription
scription factors which play a key role in the factors can occur via a number of different
induction of specific genes in response to a mechanisms (Fig. 5) which can involve ligand
specific stimulus. Thus, in the case of the cyto- binding, alterations in protein-protein inter-
kine IL-6, the synthesis of a specific transcrip- action and transcription factor phosphoryl-
tion factor NFCL-60 is induced in response to ation. Thus, for example. in the case of the

(a) Factor inactive

cl
Geneitlahe

(b) Fadoc inactim

(c) Factor iMctive

Fig. 5. Mechanisms by which transcription factors can be activated by post-translational changes.

1310 David S. Latchman

steroid receptors discussed by Tenbaum and phosphorylation results, however, in CREB

Baniahmad (this issue), the inactive receptor is being able to bind another protein CBP which
associated with an inhibitory protein hsp90. does not bind to unphosphorylated CREB.
Following binding of the steroid hormone This CBP factor appears to play a critical
ligand, hsp90 dissociates and the receptor moves role in the activation of transcription. Thus,
to the nucleus where it can bind to its appropri- this factor is able to bind to specific com-
ate response element and switch on transcrip- ponents of the basal transcriptional complex
tion. Similar dissociation of an inhibitory thereby linking CREB to this complex and
protein allowing DNA binding by the active allowing stimulation of its activity following
transcription factor also occurs for the hypoxia cyclic AMP treatment (Kwok et al., 1994). In
inducible factor HIF-1, as discussed by Wood addition, however, CBP has recently been
and Ratcliffe (this issue) and for the NFlcB fac- shown to process histone acetyl transferase ac-
tor, as discussed by Perkins (this issue). tivity (Ogryzko et al., 1996). Such enhanced
Interestingly, however, in this latter case the acetylation of histones has been shown to
dissociation of the inhibitory protein IreB from occur in regions of DNA which are active or
the NFKB is mediated via the phosphorylation potentially active in transcription (for review,
of the IlcB protein which results in its dis- see Turner, 1993) and to be involved in the
sociation from NFKB and targets it for rapid open chromatin structure characteristic of
degradation. Hence, in this case, the mechan- such regions. It is therefore possible that the
isms of regulatory protein-protein interaction binding of CBP to CREB recruits it to the
and transcription factor phosphorylation are DNA and allows it to produce changes in the
combined. chromatin structure which facilitate enhanced
Transcription factor phosphorylation is also transcription.
involved in the post-translational activation of Hence, in a specific cell type or in response
the NFIL-6 and STAT-3 factors following to a specific stimulus, specific transcription fac-
treatment by IL-6, which was discussed above tors are either synthesised or become activated
and in the article by Akira et al. (this issue). following post-translational modification. The
Thus, following exposure to IL-6, the NFIL-6 binding of these transcription factors to their
factor is phosphorylated on a specific threo- appropriate recognition sequences thus pro-
nine residue by the mitogen activated protein duces specific patterns of gene transcription
kinase (Nakajima et al., 1993) whilst the and is responsible for the observed dependence
STAT-3 factor is phosphorylated on a tyrosine of particular patterns of gene activity on
residue by Jak family kinases (Lutticken et al., specific DNA binding sequences, which was
1994). In the case of STAT-3, such phos- discussed in the introduction.
phorylation allows the STAT-3 factor to
dimerise and move to the nucleus where it can TRANSCRIPTION FACTORS AND DISEASE
switch on specific gene expression (for review,
see Ihle and Kerr, 1995). Given the vital role of transcription factors
A similar regulation of transcription factor in a wide variety of cellular processes, it is not
activity by phosphorylation is seen in the case surprising that alterations in these factors can
of the CREB factor which binds to the cyclic result in human disease (for review, see
AMP response element (CRE) and plays a Latchman, 1996a). Such diseases can con-
critical role in the regulation of transcription veniently be divided into three major groups.
in response to cyclic AMP as discussed by
Sassone-Corsi (this issue). Thus, following Developmental disorders
treatment with cyclic AMP, the CREB factor A number of developmental abnormalities
becomes phosphorylated on a serine residue at have been shown to result from mutations
position 133 (for review, see Lalli and which result in the inactivation of specific
Sassone-Corsi, 1994). transcription factors. Thus, for example, mu-
Unlike the other situations discussed so far, tations in the gene encoding the POU family
however, such phosphorylation does not result transcription factor Pit-l have been identified
in enhanced ability of CREB to bind to the in patients with combined pituitary hormone
CRE. Indeed, CREB is already bound to the deficiency in whom there is no production of
CRE before exposure of cells to cyclic AMP growth hormone, prolactin and thyrotropin
but is unable to activate transcription. Such resulting in mental retardation and growth de-
 Transcription factors: an overview 131 I

ficiency (Radovic et al., 1992). Similarly, sev- stimulate cellular growth whilst others inhibit
eral different diseases have been shown to it. Cancer can thus arise from the aberrant ac-
result from mutations in the genes encoding tivation of specific genes encoding growth pro-
members of the PAX family of transcription moting factors. These genes are therefore
factors which are discussed by Barr (this known as oncogenes (for review, see Bourne
issue). Thus, for example, mutations in PAX-3 and Varmus, 1992). Similarly, cancers also
result in Waardenburg’s syndrome (Tassabehji arise due to the inactivation of genes encoding
et al., 1992) whilst mutations in PAX-6 are as- growth inhibiting proteins which are known as
sociated with eye defects such as anirida anti-oncogenes (for review, see Knudson,
(Glaser et al., 1992). 1993). Interestingly, some oncogenes and anti-
Interestingly, such mutations resulting in oncogenes encode transcription factors which
developmental defects can also affect non-DNA exert their effects by modulating transcription
binding co-factors as well as DNA binding tran- of other specific genes.
scription factors. This is seen in the case of the As with other oncogenes, cancers caused by
CBP factor which was discussed above where it oncogenes which encode transcription factors
was indicated that it binds to the DNA binding arise when such genes are expressed at higher
CREB factor via a protein-protein interaction levels than normal or alternatively are mutated
and is essential for transcriptional activation. so that they encode a protein with abnormal
Thus, inactivation of the gene encoding CBP activity.
results in Rubinstein-Taybi syndrome invol- In humans, such changes have been most
ving mental retardation and various physical intensively characterized in different leukemias
abnormalities (Petrij et al., 1995); (for review, in which genes encoding specific oncogenic
see D’Arcangelo and Curran, 1995). transcription factors have been involved in
Hence, a variety of developmental disorders chromosomal rearrangements, so that they are
can arise from inactivation of transcription fac- either expressed at a higher level or become
tors by mutation. It is likely, however, that fused to a part of another protein. A novel
such mutations which allow live individuals to protein with oncogenic activity is therefore
be born represent the tip of the iceberg of tran- produced (for review, see Rabbitts, 1994).
scription factor mutation with the inactivation Such chromosomal rearrangements are of‘ par-
of many genes encoding transcription factors ticular importance in the case of acute and
producing such a severe defect that it is not chronic myeloid leukaemia. They also occur,
compatible with the individual’s survival. however, in solid tumours and this is discussed
in the article by Barr (this issue).
Disorders of the hormone response In contrast to oncogenes, cancer occurs in
As discussed above, the receptors for many the case of anti-oncogenes where the anti-onco-
steroid hormones and related molecules such gene is inactivated by mutation or deleted com-
as thyroid hormone are transcription factors pletely. Mutations in one such oncogene. that
which, following binding of the hormone, bind encoding the transcription factor ~53, are par-
to specific response elements and activate tran- ticularly common in cancers and it has been
scription. Clearly, therefore, mutations in the estimated that the majority of human cancers
genes encoding such receptors which interfere contain mutations in the p53 gene (Berns et ~1..
with this process will result in disorders of the 1994). When taken together with the existence
response to that particular hormone. These of other anti-oncogenes, encoding transcription
disorders are discussed in detail in the article factors such as the retinoblastoma gene (for
in this issue by Tenbaum and Baniahmad review. see Weinberg, 1993) and the Wilms’
(1997) which indicates that such mutations can tumour gene (for review, see Hastie, 1993). as
affect a wide variety of different receptors and well as the existence of many oncogenic tran-
produce very severe phenotypes. Thus, for scription factors, it is clear that alterations in
example, individuals carrying mutant thyroid such transcription factors are likely to be
hormone receptors exhibit mental retardation involved in virtually all human cancers.
and growth defects.
CONCLUSION
Cancer
The growth of cells is controlled by the In this introductory article, I have
action of a variety of proteins, some of which attempted to provide an overview of the man-
 1312 David S. Latchman

ner in which transcription factors act, the way Latchman D. S. (1996a) Transcription factors mutations
in which they are regulated and the alterations and disease. Near Eng. J. Med. 234, 28-33.
Latchman D. S. (1996b) Inhibitory transcription factors.
in them which can result in disease. All these
ht. J. Biochem. Cell. Biol. 28, 965-974.
processes are discussed in more detail in the Littlewood T. and Evan G. (1995) Helix-loop-helix.
various review articles and original papers Protein Prqjiie 2, 62 l-702.
which make up this issue. It should be clear, Lutticken C.. Wegenka U. M., Yuan J., Buschmann J..
however, from this introductory article that Schindler C.. Ziemiecki A., Harpur A. G., Wilks A. F..
Yasukawa K., Taga T., Kishimoto T., Barbieri G.,
transcription factors are vital to the process of
Pellegrini S., Sendtner M., Heinrich P. C. and Horn
transcriptional control of gene expression F. (1994) Association of transcription factor APRF and
which in turn underlies normal embryonic protein kinase Jakl with the interleukin-6 signal trans-
development, the creation and maintenance of ducer gp130. Science 263, 89-92.
tissue specific protein synthesis and the re- Mitchell P. J. and Tjian R. (1989) Transcriptional regu-
lation in mammalian cells by sequence specific DNA
sponse to specific cellular signalling pathways.
binding proteins. Science 245, 371-378.
Nakajima T., Kinoshita S., Sasagawa T., Sasaki K.,
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