sion through the Gj phase of the cell cycle, it was 
surprising to find that many of these "early" genes 
are expressed for extended periods during the he- 
patic growth response. Dr. Taub's laboratory has de- 
fined several patterns of expression of immediate- 
early, delayed-early, and liver-specific genes during 
a 9-day period posthepatectomy. 
One pattern of induction parallels the major 
growth period of the liver that ends at 60-72 hours 
posthepatectomy. A second pattern has two peaks 
coincident with the first and second Gj phases of the 
two hepatic cell cycles. A third group, which in- 
cludes liver-specific genes such as C/EBPa, shows 
maximal expression after the growth period. 
Although the peak in DNA synthesis in nonparen- 
chymal cells occurs 24 hours later than in hepato- 
cytes, most of the genes studied demonstrate similar 
induction in both cell types. This suggests that the 
Gq-Gj transition occurs simultaneously in all cells in 
the liver, but that the Gj phase of nonparenchymal 
cells may be relatively prolonged. 
Through these analyses Dr. Taub and her col- 
leagues have been able to define the temporal 
boundary between proliferation and return to quies- 
cence in the posthepatectomy liver. 
PRL-1, a Novel Type of Nuclear /Cytoplasmic 
Protein-Tyrosine-Phosphatase Induced 
in the Growth Response 
Control of the phosphorylation state of cellu- 
lar proteins is critical for normal cell growth. 
Immediate-early genes also play an important 
role in cell growth regulation. One of the 
immediate-early genes that the laboratory iden- 
tified, PRL-1, is induced in mitogen-stimulated 
cells and regenerating liver but is constitutively 
expressed in insulin-treated rat H35 hepa- 
toma cells that show normal induction of most 
immediate-early genes. 
Sequence analysis revealed that PRL- 1 encodes a 
novel 1 9-kDa protein that contains the eight-amino 
acid active site of the consensus protein-tyrosine- 
phosphatase (PTPase). PRL-1 has no homology to 
other PTPases outside this domain, leading to the 
conclusion that it is a member of a new class of 
PTPases. Bacterially expressed PRL-1 is able to de- 
phosphorylate the phosphotyrosine analogue p- 
nitrophenylphosphate (PNPP) but shows no activity 
for serine-threonine phosphorylated substrates. 
PRL-1 itself contains consensus sites for tyrosine 
phosphorylation, is phosphorylated in vitro by src 
kinase, and shows some ability to autodephosphor- 
ylate. Antibody localization studies indicate that 
PRL-1 is present in both cytoplasmic and nuclear 
fractions of cells. 
Among the products of immediate-early genes, 
PRL- 1 is the first PTPase to be identified and, like the 
cdc25 family of nuclear PTPases, may have an im- 
portant role in cell cycle regulation in the mamma- 
lian growth response. 
Transcriptional Regulators Active During 
Liver Regeneration: LRF-1 and Rat IxBa 
Understanding the basis for transcriptional re- 
sponses during liver regeneration is of major im- 
portance in understanding cell growth. Dr. Taub 
and her colleagues have identified a novel, abun- 
dant immediate-early gene that encodes a 21-kDa 
leucine zipper-containing protein designated 
LRF-1 (liver regeneration factor). In regenerating 
liver, LRF-1, JunB, c-Jun, and c-Fos among Jun/ 
Fos/LRF-1 family members are induced posthepa- 
tectomy. In liver cells, a high level of c-Fos/c-Jun, 
c-Fos/JunB, LRF-1 /c-Jun, and LRF-1 /JunB com- 
plexes are present for several hours after the Go/ 
Gi transition, and the relative level of LRF-1 /JunB 
complexes increases during G,. 
Dr. Taub and her colleagues find dramatic differ- 
ences in promoter-specific activation by LRF-1 and 
c-Fos-containing complexes. LRF-1 in combination 
with either Jun protein strongly activates a cAMP 
response element (CRE) -containing promoter that 
c-Fos/Jun does not activate. LRF-1 /c-Jun, c-Fos/ 
c-Jun, and c-Fos/JunB activate specific AP-1 and ATF 
site-containing promoters, and in contrast, LRF-1/ 
JunB potently represses c-Fos/c-Jun-mediated acti- 
vation of these promoters. 
Repression is dependent on a region in LRF- 1 that 
includes amino acids 40-84 and the basic/leucine 
zipper domain and, similarly, on a region of JunB 
that includes amino acids 186-257 and the basic/ 
leucine zipper domain. As the relative level of 
LRF- 1 /JunB complexes increases posthepatectomy, 
c-Fos/Jun-mediated ATF and AP-1 site activation is 
likely to decrease with simultaneous transcriptional 
activation of the many liver-specific genes whose 
promoters contain CRE sites. Thus, through com- 
plex interactions between LRF-1, JunB, c-Jun, and 
c-Fos, control of delayed gene expression may be 
established for extended times during the Gj phase 
of hepatic growth. 
Dr. Taub and her colleagues found that a highly 
induced immediate-early gene in regenerating liver 
encodes RL/IF-1 (regenerating liver inhibitory fac- 
tor), is the rat homologue of human MAD-3 and 
probably of chicken pp40, and has now been desig- 
nated rat I/cBa. I/cBcv has kB activity of broad speci- 
ficity in that it inhibits the binding to /cB sites of 
p50/p65 NF-zcB, c-Rel/p50, and RelB/p50, but not 
p50 homodimeric NF-/cB. Although I/cB is a cytoplas- 
GENETICS 271 
