Page 253 - Color Atlas of Biochemistry

P. 253

244 Molecular genetics

Transcriptional control ent proteins are involved in the basal com-
plex. This alone, however, is still not suf cient
Although all cells contain the complete ge- for transcription to start. In addition, positive
nome, they only use a fraction of the informa- signals have to be emitted by more distant
tion in it. The genes known as “housekeeping trans-active factors, integrated by the coacti-
genes,” which code for structural molecules vator/mediator complex, and passed on to the
and enzymes of intermediate metabolism, are basal complex (see B).
the only ones that undergo constant tran- Theactualsignalfor starting elongation
scription. The majority of genes are only ac- consists of the multiple phosphorylation of a
tive in certain cell types, in specific metabolic domain in the C-terminal region of the poly-
conditions, or during differentiation. Which merase. In phosphorylated form, it releases
genes are transcribed and which are not is itself from the basal complex along with a
regulated by transcriptional control (see also few TFs and starts to synthesize hnRNA.
p. 118). This involves control elements (cis-
active elements) in the gene’s promoter re-
gion and gene-specific regulatory proteins B. Regulation of PEP-CK transcription
(transcription factors, trans -active factors), Phosphoenolpyruvate carboxykinase (PEP-CK),
which bind to the control elements and a key enzyme in gluconeogenesis, is regulated
thereby activate or inhibit transcription. by several hormones, all of which affect the
transcription of the PEP-CK gene. Cortisol,
glucagon, and thyroxin induce PEP-CK, while
A. Initiation of transcription
insulin inhibits its induction (see p. 158).
In the higher organisms, DNA is blocked by More than ten control elements (dark red),
histones (see p. 238) and is therefore not ca- distributed over approximately 1 kbp, have so
pable of being transcribed without special far been identified in the promoter of the PEP-
positive regulation. In eukaryotes, it is there- CK gene (top). These include response ele-
fore histones that play the role of repressors ments for the glucocorticoid receptor (GRE;
(see p. 118). For transcription to be set in mo- seep. 378),for thethyroxin receptor(TRE),
tion at all, the chromatin first has to be re- and for the steroid-like retinoic acid (AF-1).
structured. Additional control elements (CRE, cAMP-re-
In the resting state, the lysine residues in sponsive element) bind the transcription fac-
the N-terminal “tail” of the histones (see tor C/EBP, which is activated by cAMP-de-
p. 238) are not acetylated. In this state, which pendent protein kinase A through phosphor-
can be produced by histone deacetylases [1], ylation. This is the way in which glucagon,
the nucleosomes are stable. It is only the in- which raises the cAMP level (see p. 158),
teraction of activator and regulator proteins works. Control element P1 binds the hor-
with their control elements that allows the mone-independent factor NF-1 (nuclear fac-
binding of coactivator complexes that have tor-1). All proteins that bind to the control
histone acetylase activity [2]. They acetylate elements mentioned above are in contact
the histone tails and thereby loosen the nu- with a coactivator/mediator complex (CBP/
cleosome structure suf ciently for the basal p300), which integrates their input like a
transcription complex to form. computer and transmits the result in the
This consists of DNA-dependent RNA poly- form of stronger or weaker signals to the basal
merase II and basal transcription factors transcription complex. Inhibition of PEP-CK
(TFIIX, X = A – H). First, the basal factor TFIID transcription by insulin is mediated by an
binds to the promoter. TFIID, a large complex insulin-responsive element (IRE) in the vicin-
of numerous proteins, contains TATA box- ity of the GRE. Binding of an as yet unknown
binding protein (TBP) and so-called TAFs factor takes place here, inhibiting the binding
(TBP-associated factors). Thepolymeraseis of the glucocorticoid receptor to the GRE.
attached to this core with the help of TFIIB.
Before transcription starts, additional TFs
have to bind, including TFIIH, which has heli-
case activity and separates the two strands of
DNA during elongation. In all, some 35 differ-

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