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38 Part I Molecular and Cellular Basis of Hematology

TATA box Exon Intron
Enhancer Promoter Enhancer

Transcription

Splicing

Finished transcription product
cap -AAAAAAAAA

Translation into protein product

Fig. 4.1 OVERVIEW OF GENE TRANSCRIPTION FROM DNA TO RNA AND THEN TRANSLA-
TION FROM RNA TO PROTEIN. Protein synthesis requires multiple processes and regulatory steps
including transcript of DNA into RNA, splicing and posttranscription modification of RNA, translation of
RNA into protein, and posttranslational protein modification.

far from either side of the gene, or even within it. This means that Transcription of the different classes of RNAs in eukaryotes is carried
there may be several signals determining whether a certain gene can out by three different RNA polymerase enzymes. RNA polymerase
be transcribed. In fact, multiple enhancer sites may be linked to one I synthesizes the rRNAs, except for the 5S species. RNA polymerase
gene, and each enhancer may be bound by more than one transcrip- II synthesizes the mRNAs and some small nuclear RNAs (snRNAs)
tion factor. Whether or not such a gene is transcribed is the sum of involved in RNA splicing. RNA polymerase III synthesizes 5S rRNA
the activity of these transcription factors bound to the different and tRNAs.
enhancers. Enhancers can compensate for a weak promoter by The most intricate controls of eukaryotic genes are those that
binding activator transcription factors. For instance, regulation of govern the expression of RNA polymerase II–transcribed genes, the
gene expression during T-lymphocyte differentiation requires multiple genes that encode mRNA. Most eukaryotic mRNA genes contain a
activating transcription factors, such as lymphocyte enhancer factor basic structure consisting of alternating coding exons and noncoding
(LEF-1), GATA-3, and ETS-1, binding to the T-cell receptor alpha introns, and have one of two major types of basal promoters, as
gene (TCRA) enhancer. defined earlier. These protein-coding genes also can have a variety of
Transcription factors can also influence multiple genes in coordi- transcriptional regulatory domains, such as the enhancers or silencers
nation, like the globin family. Enhancers are often the major deter- mentioned previously. In addition to management of gene expression
minant of transcription of developmental genes in the differing by the binding strength of the RNA polymerase promoters at the
lineages and stages of hematopoiesis. They can also inhibit transcrip- beginning of a given gene, the interaction between activator and
tion of specific genes in one cell type while at the same time activating inhibitor transcription factor proteins binding to the given promoter
it in another cell type. When gene sequences routinely negatively also exerts regulatory action on transcription.
regulate gene transcription, they are termed silencers, not enhancers. To initiate transcription, the RNA polymerase must bind to the
Another type of DNA regulatory sequence is called insulators. These promoter sequence. However, as mentioned earlier, this can only
define borders of multigene clusters to prevent activation of one set happen with help from gene-specific transcription factors that
of genes from affecting a nearby set of genes in another cluster. mediate RNA polymerase binding to the promoter. These transcrip-
tion factors are sequence-specific DNA binding proteins that can be
modified by cell signals. Many transcription factors, such as signal
TRANSCRIPTION OF GENES transducer and activator of transcription (STAT) proteins, require
phosphorylation in order to bind DNA. Because transcription factors
The first phase of gene expression occurs when the RNA polymerase can be targeted by kinases and phosphatases, phosphorylation can
synthesizes RNA from a DNA gene template, which, as described effectively integrate information carried by multiple signal transduc-
in the previous section, is called transcription. The encoded material tion pathways, thus providing versatility and flexibility in gene regula-
on the transcribed gene determines the kind of RNA synthesized. tion. For example, the Janus kinase (JAK)–STAT pathway is widely
For example, proteins are coded for by messenger RNA (mRNA), used by members of the cytokine receptor superfamily, including
which will later undergo the process of translation. Alternatively, the those for granulocyte colony-stimulating factor (G-CSF), erythropoi-
transcribed gene may encode transfer RNA (tRNA), which carries etin, thrombopoietin, interferons, and interleukins. Normally,
specific amino acids to the ribosome for incorporation into the ligand-bound growth factor receptors lead to JAK2 phosphorylation,
growing protein chain during translation. Another type of RNA which then activates STAT, also by phosphorylation. Activated STAT
synthesized from genes in DNA is ribosomal RNA (rRNA), which then dimerizes, translocates to the hematopoietic cell nucleus, binds
serves as the backbone of ribosomes and interacts with tRNA during DNA, and promotes transcription of genes for hematopoiesis. Altera-
translation. Ribosomes catalyze the formation of proteins using the tion of JAK2, such as a V617F mutation, results in a constitutively
mRNA as the code and the tRNA to obtain the amino acids to build active kinase capable of driving STAT activation. This leads to con-
the proteins. Each amino acid is attached to the previous one by stitutive transcription of STAT target genes, and results in myelopro-
hydrolysis and aminotransferase activity residing within the ribosome. liferative disorders such as polycythemia vera.