Biology Reference
In-Depth Information
27
The DLC Suppressor Genes
The deleted in liver cancer (DLC) gene, so named because of the original finding
that it was deleted in liver cancer, has come to be established as a suppressor of
many tumour types. DLC1 is one of a cluster of six genes on chromosome 8 deleted
in liver cancer and along with some other genes demonstrated to reflect tumour pro-
gression and poor prognosis (Roessler et al., 2012). DLC1 is a member of a fam-
ily comprising three proteins that function as Rho-GAP (GTPase-activating proteins)
by virtue of the GAP domain and so actively involved in the regulation of cell pro-
liferation, modulation of cytoskeletal dynamics and cell migration. DLC1 requires
Rho-GAP activity to exert its suppressor function, but this is probably insufficient
for complete tumour suppression (Sekimata et al., 1999; Wong et al., 2005; Yam
et al., 2006). DLC1 interacts with and potentiates the activity of PLCD1 (phospholi-
pase C1δ) (Homma and Emori, 1995) and PLCD1 is itself a tumour suppressor (see
pp. 195-197). Deregulated function of the DLC proteins leads to cell transforma-
tion with attendant aberrant cell behaviour. Loss of expression occurs by deletion,
promoter methylation or mutations (Liao et al., 2008; Yuan et al., 2003a,b). The
suppressor function of DLC1 may be abrogated also by PI3K/Akt-mediated phos-
phorylation (Ko et al., 2010).
DLC1 and DLC2 show significant homology and share the same domain struc-
ture, namely a Rho-GAP domain, a SAM (sterile alpha motif domain related to
p73/p63/p53 family SAM domain containing proteins) and a lipid-binding START
(StAR-related lipid transfer) domain. Whether DLC2 has similar tumour suppressor
ability as DLC1 is yet undetermined. Both the genes are suppressed in a number of
human tumours. Early work by Ching et al. (2003) showed that DLC2 is downregu-
lated in human HCC, probably at a lower frequency than DLC1 is reported to be.
But DLC2 does possess GAP activity specific for small GTPases RhoA and Cdc42.
Furthermore, the GAP domain inhibited the formation of actin stress fibres by Rho
mediation and suppressed Ras-mediated cell transformation. Holeiter et al. (2008)
found that whilst loss of DLC1 enhanced migration, suppression of DLC2 had no
effect on cell migration. According to Yau et al. (2009), DLC2 deficiency did not
make host mice prone to chemically induced tumorigenesis. Holeiter et al. (2008)
believe that the differences in their suppressor function might be related to the sub-
cellular distribution. DLC3 is a third member of the family with tumour suppres-
sor function. It is expressed in normal tissues but markedly downregulated in several
forms of cancer (Durkin et al., 2007).
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