Biology Reference
In-Depth Information
29
PLCD1 Suppresses
Tumorigenesis
The PLCD1 (phospholipase Cδ1), a member of the phospholipase C family, which
together with other members PLCγ, PLCζ, PLCη and PLCε, converts phosphati-
dylinositol 4,5-bisphospate to diacylglycerol (DAG) and inositol 1,3,5-trisphosphate
(IP3), both possessing second messenger function. IP3 regulates intracellular Ca
2+
levels by mobilising calcium from intracellular endoplasmic reticulum-associated
stores and probably also by stimulating Ca
2+
influx into cells. The transduction of
signals imparted to the cell by the binding of extracellular ligands to their respec-
tive membrane receptors generates repetitive calcium spikes or oscillations and these
transient increases of intracellular calcium are mediated by IP3. Such calcium oscil-
lations occur in many physiological phenomena. IP3R are required for IP3-mediated
mobilisation of calcium from intracellular stores, but not for calcium influx. A vari-
ety of biological response modifiers transduce their signals via cytoskeletal structure
and IP3 signalling has obvious links with cytoskeletal dynamics.
Deregulation of IP3 and downstream calcium signalling has serious consequences
for biological responses in developmental systems as well in pathogenesis (Sherbet,
2001). DAG promotes RasGRP (Ras guanyl nucleotide-releasing protein)-mediated
Ras-GDP to Ras-GTP exchange activity, and this leads to the activation of the
Ras/MEK/ERK signalling cascade to generate phenotypic effects of cell proliferation
and differentiation. By another route DAG can activate Rac-GTP signalling to influence
cytoskeletal dynamics, cell migration, adhesion and invasion (Griner and Kazanietz,
2007). With such important signalling connections and its loss in many tumour types,
PLCD1 has earned the epithet of tumour suppressor.
Loss of PLCD1 Expression in Tumours and its
Biological Outcome
The tumour suppressor function of PLCD1 is reinforced by the perceived loss of its
expression in several tumour types, such as oesophageal squamous cell carcinomas,
gastric and colon cancers. But there is some uncertainty in relation to the status of its
expression in breast cancer. The PLCD1 gene is located on chromosome 3p22.3 and
this happens to be one of the regions frequently deleted in oesophageal squamous cell
carcinoma. Loss of expression was encountered in 26/50 carcinomas and 4/9 tumour
cell lines. This resulted from promoter methylation or loss of one or both alleles or
loss of an allele plus methylation of the second (Fu et al., 2007). Of particular interest
is the correlation noticed between loss of expression and dissemination of tumour to
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