Signal Transduction Pathways in B Lymphocytes 
(i.e., pelle and tube) are probably components of 
the signal transduction pathway that resuh in the 
modification of cactus. The challenge for the fu- 
ture is to find the analogues of pelle and tube in 
mammalian cells, and we are exploring difl'erent 
approaches in our attempt to elucidate the signal 
transduction pathway that results in the constitu- 
tive activation of NF-/cB in mature B cells. 
The next major advance was the cloning of I/cB, 
and once again the cloning revealed a sequence 
homology that is important for I/cB function. In 
this case the sequence elements are the ankyrin 
repeats that are found in a diverse group of pro- 
teins, including the pi 05 precursor of NF-/cB 
p50, Drosophila Notch, yeast cdclO, and the hu- 
man erythrocyte ankyrin protein. Because all of 
these proteins are either cytosolic or membrane 
associated, the initial idea was that ankyrin se- 
quences mediate cytosolic retention of proteins 
by binding to cytosolic or membrane structures. 
However, a nuclear transcription factor was re- 
cently found to contain these sequences, necessi- 
tating a change in our idea of the role of ankyrin 
sequences. A more comprehensive model envi- 
sions them as domains responsible for protein- 
protein interaction. We also found that pp40, a 
protein associated with v-Rel and c-Rel in 
chicken lymphoid cells, is a homologue of mam- 
malian IkB. This observation, along with the find- 
ing that cactus is also homologous to I/cB, sug- 
gests that the NF-KB/rel/dorsal family has 
evolved over millions of years and used the same 
general principles for regulating the activity of 
these positive-acting transcription factors. 
One of the most interesting questions about 
NF-/(B is its regulation during B cell development. 
NF-kB is an inducible cytosolic protein in pre-B 
cells but changes into a constitutively active nu- 
clear protein in mature B cells. There can be at 
least two simple explanations for this: either a 
transcriptional shutofl" of I/cB synthesis or a con- 
stitutive modification of I/cB in mature B cells. 
Preliminary results indicate that transcription of 
the major form of I/cB is not shut off in mature B 
cells, but the UB that is synthesized is somehow 
inactivated. We are trying to determine how IkB 
activity is regulated in mature B cells. We also 
want to determine the signal responsible for the 
developmental transition of a pre-B cell to a ma- 
ture B cell. 
The other major focus of our research is to un- 
derstand the regulation of k gene expression in 
plasma cells. Unlike mature B cells, plasma cells 
express large amounts of the immunoglobulin 
chains, including the k chains, which form com- 
plete immunoglobulin molecules that are se- 
creted. The high-level expression of the k gene is 
not driven by the intronic enhancer; instead, an 
enhancer located 9 kb downstream of the k gene 
appears to be the dominant element in plasma 
cells. Therefore k expression appears to be con- 
trolled by a unique dual enhancer system during 
development: the intronic enhancer drives low- 
level expression in mature B cells, while the 3' 
enhancer is responsible for high-level expression 
in plasma cells. The questions we wish to address 
in this system are, What is the protein(s) responsi- 
ble for the activity of the 3' enhancer in plasma 
cells? WTiat is the signal that activates the 3' en- 
hancer? and finally. What role does crosslinking 
of the surface immunoglobulins play in this pro- 
cess? We would also like to study the surface im- 
munoglobulin complex on mature B cells that in- 
cludes proteins such as mb-1 and B-29 and 
elucidate the signal transduction pathway that 
leads to the activation of the 3' enhancer. 
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