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CRSP3 Metastasis Suppressor
The CRSP3 (also known as CRSP130, DRIP130, ARC130, among others) protein
is encoded by the gene MED23. CRSPs (cofactor required for SP1 activation) bind
to several nuclear receptors including vitamin D3 receptor (VDR), hence one of
the aliases is DRIP (an acronym for vitamin D receptor interacting protein) and
function as co-factor complexes enhancing ligand dependent transcription. CRSPs
are co-factors required for gene activation by Sp1, a zinc finger transcription fac-
tor that binds to GC-rich motifs of many promoters. Sp1 transcription factor is an
activator or repressor of transcription of numerous genes involved in cell prolif-
eration, apoptosis, cell differentiation and immune response. It is hardly surpris-
ing that CRSP3 as a co-factor required for Sp1 activation should be linked with
the cancer phenotype. Importantly, Sp family members participate in activation
of VEGF gene transcription (Abdelrahim et al., 2004). The expression of Sp1
has been shown to correlate closely with VEGF expression in human NSCLCs,
and further hypoxia increases Sp1 binding to the VEGF promoter (Deacon et al.,
2012). Consistent with these findings, Sp1 levels have directly correlated with
expression of VEGF and with microvascular density. Knockdown of Sp1 led to
inhibited growth and metastasis of pancreatic cancer cells growing as xenografts
(Yuan et al., 2007). So without much ado, one can conclude that Sp1 and related
transcription factors are liable to be active participants in the tumour progression
to the metastatic state. However, one should be mindful that VEGF is regulated by
many suppressor genes including MKK and ID (see pp. 137-140; 204-208).
CRSPs interact with regulatory proteins and function as a scaffold for the for-
mation of the pre-initiation complex with RNA polymerase II and the transcription
factors. The recognition of CRSP3 as a metastasis suppressor follows ostensibly
from attempts aimed at identifying potential upstream regulators and downstream
effectors of KiSS metastasis suppressor gene. The attribution of the ability to sup-
press metastasis derives from the demonstration that cells transfected with CRSP3
showed upregulation of the metastasis suppressor genes KiSS1 and TXNIP (thiore-
doxin interacting protein). Also loss of CRSP3 correlated with loss of KiSS1 expres-
sion in melanoma samples (Goldberg et al., 2003). Loss of CRSP3 in melanoma
cells led to a reduction of activation of the KiSS1 promoter. When Sp1 and CRSP3
were co-expressed, KiSS1 suppressor activity was reinstated in cancer cells leading
to inhibition of invasive behaviour. Furthermore, Sp1 bound to a specific GC-rich
region in the KiSS1 promoter to regulate expression of the gene, since deletion of
this motif interfered with the regulatory process (Mitchell et al., 2007). Overall, the
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