The involvement of
phospholipids and in particular
polyphosphoinositides in cellular signalling has been documented in detail in the last 20 years. In addition to the plasma membrane localization also the nucleus is shown to be a site for both synthesis and hydrolysis of the phosphorylated forms of
phosphatidylinositol. Previous observation have established that the nucleus possesses a specific PLC for
inositol lipids, i.e., the
PLC beta 1
isoform, which undergoes rapid and transient activation after
IGF-I stimulation of quiescent Swiss 3T3 cells and is down-regulated
after treatment of Friend
erythroleukemia cells with
DMSO. Here we have reviewed: (i) the potential of nuclear
PLC beta 1 to be a target for anti-
cancer drug, (ii) the capability of this PLC
isoform, when activated by
IGF-I, to be a key signalling molecule in the onset of
DNA synthesis, via DAG generation and PKC alpha translocation to the nucleus, (iii) the chromosome mapping of
PLC beta 1 gene. The differentiation program of Friend cells can be activated by other agents besides
DMSO including
tiazofurin, an anti-
tumor drug, also capable of affecting the nuclear
inositol lipid cycle.
Tiazofurin induces a lowering of the activity of
PLC beta 1 due to down regulation of this
isoform as revealed by both Western blotting and Northern blotting analyses. Using Swiss 3T3 cells stably transformed with an antisense
PLC beta 1 construct, the knock-out of the
PLC beta 1 gene induces both a loss of
PLC beta 1 expression, as determined by Western blots, and a loss of the mitogenic responsiveness to
IGF-I. These events show a direct relationship between nuclear
PLC beta 1 evoked signals and
IGF-I induced cell proliferation. Finally, the assignment of the
PLC beta 1 gene to the band q35-36 of rat chromosome 3 paves the way for further genetic studies given the fact that the region where
PLC beta 1 gene maps is a hot spot for genetic alterations in a number of experimentally induced rat
tumors. Taken as a whole, these results assign a key role to the regulation of nuclear PLC activity and expression both in
growth-factor activated mitogenesis and in in vitro erythroid differentiation.