The small MAFs, MAFF, MAFG and MAFK have emerged as crucial regulators of mammalian gene expression. Previous studies have linked small MAF function, by virtue of their heterodimerization with the Cap 'n' Collar (CNC) family of transcription factors, to the stress response and detoxification pathways. Recent analyses have revealed a complex regulatory network involving small MAF transcription factors and other cellular proteins. The expression and activity of small MAFs are tightly regulated at multiple levels. With regard to their clinical importance, small MAFs have been linked to various diseases, such as diabetes, neuronal disorders, thrombocytopenia and carcinogenesis. A better understanding of the molecular mechanisms governing the activity of small MAFs will provide novel insights into the control of mammalian transcription and may lead to the development of novel therapeutic strategies to treat common human disorders.
We have constructed a very large virtual diversity space containing more than 10(13) chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.
Cytokines play key roles in a variety of reproductive processes including normal parturition as well as preterm birth. Our previous data have shown that
MAFF
, a member of the
MAF
family of
bZIP
transcription factors, is rapidly induced by pro‐inflammatory cytokines in
PHM
1‐31 myometrial cells. We performed loss‐of‐function studies in
PHM
1‐31 cells to identify
MAFF
dependent genes. We showed that knockdown of
MAFF
significantly decreased
CXCL
1 chemokine and
CSF
3 cytokine transcript and protein levels. Using chromatin immunoprecipitation analyzes, we confirmed
CXCL
1
and
CSF
3
genes as direct
MAFF
targets. We also demonstrated that
MAFF
function in
PHM
1‐31 myometrial cells is able to control cytokine and matrix metalloproteinase gene expression in
THP
‐1 monocytic cells in a paracrine fashion. Our studies provide valuable insights into the
MAFF
dependent transcriptional network governing myometrial cell function. The data suggest a role of
MAFF
in parturition and/or infection‐induced preterm labour through modulation of inflammatory processes in the microenvironment.
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