Biology Reference
In-Depth Information
of protein expression, but where the protein is not detected no effort is made to check
if this is a consequence of translational control. It would be needless reiteration to
say that translational control has a critical role to play in development, differentia-
tion and cell proliferation. It may be recalled here that miRNAs repress translation
of mRNAs of target genes. Maspin has shown inverse correlation with miRNA-21
expression.
Notwithstanding the evidence contradictory to the suppressor function of Maspin,
it would be appropriate to emphasise the positive aspects. There is much experimen-
tal evidence linking Maspin to the suppression of cell proliferation and invasion. The
p53 pathway was implicated early on with the demonstration that p53 bound directly
to the Maspin promoter and furthermore mutant p53 inversely correlated with
Maspin expression (Zou et al., 2000; Zhang and Zhang, 2002). Maspin and the apop-
tosis related gene GADD45A (growth arrest and DNA-damage inducible) are both
regulated by p53 and the transcription factor ATF-2. Both activate Maspin transcrip-
tion by binding to separate sites on Maspin promoter. ATF-22 binds to GADD45A
via transcription factors Oct-1, NF-1 and BRCA1 (Maekawa et  al., 2008). The
operation of the MAPK signalling is obvious since ATF-2 is a target of p38/MAPK
and JNK leading to apoptosis. In contrast, mutant p53 seems to relate inversely to
Maspin (Cho et al., 2007). Possibly mutant p53 is capable of inhibiting Maspin and
abrogate its ability to impose cell cycle arrest.
As noted earlier, the transcription factor Snail promotes EMT by suppressing
E-cadherin. But Neal et al. (2012b) now show that Snail is recruited to and represses
the Maspin promoter and this is linked with increased cell motility. Other suppres-
sor might be involved with the functioning of Maspin. Suppression of Maspin alters
the expression of many genes; notable among them is BRMS1 itself a suppressor
gene (Liu et al., 2012fa). Whether this reflects a compensatory response by cells or
a result of intervention by miRNA is a matter for further exploration. MiRNAs are
known to be involved in the regulation of both Maspin and BRMS1. On the other
hand, Maspin downregulation by promoter hypermethylation correlated with reduced
Maspin protein levels and with increase of the tumour promoter protein MTA1 and
VEGF (Sharma et al., 2011).
A mode of induction of apoptosis driven by Maspin involves the DNA repair pro-
tein Ku. Ku as a heterodimer (Ku70/80) participates in non-homologous end-joining
and also in controlling transcription and apoptosis. Ku functions by interacting with
many cellular proteins and nucleic acids. It is involved in Bax-mediated apoptosis.
Ku protein levels are reduced in some neoplasms and high levels of Ku are associ-
ated with radiation resistance. In the cytoplasm, Ku70 occurs in a complex with Bax
thus sequestering the latter from inducing apoptosis. This complex depends upon
the state of acetylation of Ku70 and when it is acetylated Bax is released from the
complex (Subramanian et al., 2011). Maspin has been found to inhibit HDAC1 and
increase the acetylation of Ku70 and induce apoptosis (Lee et al., 2012).
The inhibitory effect appears to involve ECM components that determine inter-
cellular adhesion and also migration, such as the trimeric glycoprotein laminin.
Integrity of Maspin expression is essential for normal embryonic development.
It seems to regulate both cell proliferation and migration in embryonic systems.
Search WWH ::




Custom Search