Page 66 - 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

Gene Expression, Regulation of 515

protein. The shift from making a membrane-bound or
secreted antibody is regulated at the level of alternative
poly(A) site usage (Fig. 13). Thus, in the unstimulated
B cell the first poly(A) signal is ignored and the down-
stream poly(A) signal is used as the default poly(A) site.
The last two exons incorporated in the mRNA encode for
a membrane-binding domain that anchors the antibody
to the plasma membrane. After stimulation the upstream
poly(A) signal is activated resulting in the processing of
a mRNA that is translated to the same antibody but lack-
ing the membrane-binding domain. Hence this antibody is
secreted.
Also, a new translational reading frame, encoding for
a completely different protein, may be produced by alter-
native poly(A) site usage. For example, production of cal-
citonin, which occurs in thyroid cells, and the calcitonin-
related protein, which is produced in the brain, is regulated
by tissue-specific poly(A) site usage.

FIGURE 12 Model for cleavage and polyadenylation of a D. Transcription and RNA Processing
precursor-RNA in mammalian cells. The cleavage and polyadeny- Are Coordinately Regulated Events
lation specificity factor (CPSF) binds to the conserved AAUAAA
sequence located 10–35 nucleotides upstream of the poly(A) site. Recent experiments suggest that transcription and RNA
The cleavage-stimulatory factor (CStF) binds to the GU-rich ele- processing are tightly coupled events. Thus, the RNA
ment located downstream of the poly(A) site. Binding of two cleav- polymerase that assembles at the promoter has been shown
age factors (CF1 and CF II) and the poly(A) polymerase (PAP) then
stimulates cleavage of the precursor-RNA. The PAP synthesizes to associate with factors required for polyadenylation and
the 200- to 250-nucleotide-long poly(A) tail, while the downstream SR-related proteins that may partake in RNA splicing.
RNA fragment is rapidly degraded. The CTD tail of RNA polymerase II appears to func-
tion as a platform that recruits the RNA processing fac-
antibody anchored to the plasma membrane. After bind- tors to the preinitiation complex. Therefore, the elongat-
ing to an antigen the lymphocyte undergoes differentia- ing RNA polymerase appears to have been loaded with
tion and produces the same IgM molecule as a secreted the factors required for polyadenylation, and probably

FIGURE 13 Alternative polyadenylation signals in the constant region of IgM yields heavy chains that are either

membrane bound (pre-B cells) or secreted (plasma cells). Note that only the exon structure of the 3 part of the IgM
transcription unit is shown. The upstream region, which encodes for the antigen-binding domain, is identical in the
two forms of IgM.