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Another metastasis suppressor gene apparently involved in regulating the activ-
ity of KAI1 is NDRG1 (N-myc downstream-regulated gene). The latter can induce
KAI1 and suppression of NDRG1 reduces KAI1 expression. In fact loss of KAI1
diminishes the metastasis suppressor function of NDRG1. The loss of both NDRG1
and KAI1 occurs in prostate cancer progression NDGR1 also inhibits the metasta-
sis promoting transcription factor ATF3, which can modulate KAI1 transcription
(Liu et al., 2011d). ATF3 is a stress-inducible transcriptional repressor. The stress
response is mediated by JNK with NF-κB, a component of a transcription complex
containing ATF3, and MAPK or p53-dependent signalling pathway. The p53 gene
can induce transcription of ATF3. The involvement of p53 with NDRG1 signalling is
discussed in detail elsewhere in this topic (pp. 111-117). Thus taken together, a com-
plex network of signalling seems to function in bringing about a co-ordinated con-
trol of cell proliferation, intercellular/substratum adhesion, invasion and metastatic
dissemination.
Reactivation of KAI1
The reactivation of KAI1 by p53 was cited earlier. Mashimo et al. (1998) identified
a tandem repeat of the p53 consensus-binding sequence in the KAI1 promoter and
the expression of the two genes showed a strong correlation in prostate cancer and
loss of both resulted in poor prognosis. Mashimo et al. (2000) further showed that
the topoisomerase II inhibitor etoposide activated KAI1 and markedly inhibited cell
motility in human prostate cancer cell lines and a lung carcinoma cell line. These
changes occurred by the mediation of p53 or c-Jun. As one would recall, in addi-
tion to p53, binding sites for c-Jun/transcription activating factors AP1 and AP2 have
been identified in the KAI1 promoter (Marreiros et al., 2003).
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