Page 55 - Academic Press Encyclopedia of Physical Science and Technology 3rd Molecular Biology

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Encyclopedia of Physical Science and Technology EN006H-655 June 29, 2001 21:21

504 Gene Expression, Regulation of

the core promoter, so-called promoter proximal elements. basal transcription factors are sequentially recruited to the
UAS elements are typically located within 200 base pairs promoter.However,fractionationexperimentshaveshown
upstream of the transcription initiation site. Enhancer se- that on certain promoters the RNA polymerase and most
quences are DNA segments containing binding sites for or all of the general transcription factors may be recruited
multiple transcription factors that activate transcription as a single complex. In vivo activation of the thousands of
independent of their orientation and at a great distance promoters present in the human genome may use a large
[up to 85 kilobases (kb)] from the start site of transcrip- spectrum of mechanistic possibilities.
tion. Enhancer elements can be located either upstream or An important finding was the observation that UAS-
downstream of the transcription initiation site. Enhancer binding transcription factors are modular in structure with
sequences activate transcription in a position-independent a DNA-binding domain and an effector domain that could
manner because they become spatially positioned close to be exchanged without losing their predicted biological
the core promoter through bending of the DNA molecule activity. The effector or activation domains in different
(Fig. 1). transcription factors perform the same task but have dif-
In addition to enhancer elements, eukaryotic promoters ferent properties, for example, consisting of acidic blobs,
contain upstream repressor elements, which block RNA proline-rich, glutamine-rich, or serine/threonine-rich se-
synthesis by various mechanisms by recruiting factors that quences. Different classes of UAS-binding transcription
interefere with enhancer factors or directly block RNA factors may transmit a signal to the basal promoter com-
polymerase II recruitment. A third class of DNA sequence plex by making specific contacts with different TAFs. For
elements regulating transcription are the transcriptional example, an interaction between the UAS-binding tran-
silencers. A classical silencer represses transcription in scription factor SP1 and TAF-110 has been shown to
a position- and orientation-independent fashion. The si- be necessary for SP1-mediated activation of transcrip-
lencer element is thought to block transcription by func- tion. Collectively stabilized protein–protein interactions
tioning as the nucleation site for binding of histones or between UAS-binding factors and the general transcrip-
silencing proteins that coat the region, thereby making the tional factor TFIID are likely to facilitate recruitment of
promoter inaccessible for RNA polymerase recruitment. the RNA polymerase to the core promoter element, and as
The human genome encodes for several thousand dif- a consequence increase the transcriptional activity of the
ferent transcription factors. Promoters that contain com- promoter (Fig. 1).
binations of binding sites for different transcription fac- Transcription factors can be subdivided into families
tors regulate different genes. Thus, for example, a gene based on the structural feature of the DNA-binding do-
specifically expressed in the liver or the brain uses liver- main. Thus, the DNA-binding domain may interact with
or brain-specific enhancer binding transcription factors, the DNA through structural types like the helix-turn-helix
respectively, to achieve a tissue-specific gene expression. motif found in homeodomain proteins, zinc fingers, or
The basal transcriptional machinery appears to a large ex- leucine-zipper-basic DNA-binding domain motifs. Het-
tent to be the same in all cell types. erodimerization between members of UAS-activating
transcription factors belonging to such structural types is
not uncommon and has been shown to increase the reper-
B. Regulation of Promoter Activity
toire by which transcription factors can interact with dif-
From a regulatory point of view it is important to note ferent promoter sequences. For example, the prototypical
that TBP is sufficient to recruit RNA polymerase II and AP1 transcription factor, which belong to the leucine-
direct basal transcription from the core promoter. How- zipper family of transcription factors, consists of a het-
ever, the basal transcription factor TFIID has been shown erodimer of c-jun and c-fos. It binds to its cognate DNA
to play a central role in activated transcription by binding motif with a higher affinity than, for example, a c-jun–
to the TATA element in the core promoter and facilitat- c-jun homodimer or a JunB–c-fos heterodimer. The com-
ing the recruitment of the RNA polymerase holoenzyme binatorial complexity is further increased by the fact that
to the promoter (Fig. 1). TFIID is a multiprotein complex c-jun may form heterodimers with members of the ATF
consisting of TBP and approximately 11 TBP-associated family of transcription factors. Thus, heterodimerization
factors (TAFs). The TAFs have been shown to be essen- between different members of a transcription factor fam-
tial for regulated transcription by mediating contact with ily is an important mechanism to generate factors with
enhancer binding factors. Thus, TBP is sufficient for con- alternative DNA-binding specificity.
stitutive transcription but TAFs are necessary for regulated When the RNA polymerase leaves the promoter, TFIID
transcription (Fig. 1). In vitro studies suggest that assem- remains bound at the TATA element and is ready to help a
bly of an initiation-competent RNA polymerase at a pro- second RNA polymerase to bind and initiate transcription
moter can be subdivided into several steps where different at the same promoter. The activity of TFIID appears also