ADAMTS9 CRIP2 ENGASE IL23A RT1-DA AHCY CTGF ERO1LB KRT20 S100A4 AMIGO3 DDIT3 ETV5 MANF SDF2L1 ANKRD37 DERL3 FGF18 MFSD2 SEC23B ATMIN DNAJB11 FOLR1 NR4A2 SEL1L BCAM DNAJB9 GGCT NUPR1 SLIT1 BET1 DNAJC3 GMPPB PDIA4 TM4SF1 CASP4 DUOX2 HSP90B1 PRIMA1 TMEM140 CDH1 DUSP5
HSPA5 PRSS8 TMEM66 COQ10B DYNLRB2 HYOU1 RIL ZFAND2A CRELD2 ELOVL2 IGF2BP2 RIOK3 Table 3: Target genes of the transcription factor PAX8 (gene symbol) .
Of these, the upregulated genes were found to be HSPs, BAG3, SOCS3, GADD45G, GCLM, VLDLR, CYR61, DUSP1, DUSP5
, FOS, EGR1, MAFB, NR4A1, PROP1, TGFB1, DNAJB1, ADM, and DDIT3.
DUSP1, DUSP5, and DUSP6 are suggested as hypoxia-sensitive and responsible for ERK downregulation [17, 18].
Cells were transfected by commercially available siRNA against DUSP1 (sc-35938), DUSP5 (sc-60555), DUSP6 (sc-39001) transcripts (each consisting of a pool of 3 target-specific 19-25 nt siRNAs designed to knock down gene expression), or related nonsilencing control (all Santa Cruz Biotechnology, USA) using Lipofectamine RNAiMAX Reagents (Thermo Fisher Scientific Inc., USA) according to the manufacturer's instructions.
In contrast to DUSP1, the level of transcripts of DUSP5 and 6 remained unaffected in hypoxia, again independently of the presence of HIF-1[alpha] (Figures 3(b) and 3(c), resp.).
We also tested DUSP5 as a representative of nuclear inducible DUSP with specificity only towards ERK; the higher efficiency of DUSP1 in the dephosphorylation of p38 and c-Jun N-terminal kinase was described by other authors [49, 50].
Among these, the upregulation of some genes controlled by the NF-[kappa]B complex such as CCL5 (RANTES), H2-Q1 (HLA-B), the protein phosphatase DUSP5
involved in negative regulation of MAP kinases, the transcription factor FOSB, or SERPINE1 and also the downregulation of the macrophage migration inhibitory factor (MIF), CXCL1, ABCG1, SOD3, and negative regulator of NF-[kappa]B TRIB3 could represent the initial response to virus infection in the absence of viral genome replication.
DUSP5, DUSP6, DUSP8, and DUSP10 were found inside the group of middle expressed PTPs.
Interestingly, it has been proposed that the spatial distribution of dephosphorylated MAPKs is regulated by the binding of MKPs, such as the nucleocytoplasmic location of ERK by nuclear DUSP5 and cytoplasmic DUSP6, and the accumulation of ERK in the nucleus by DUSP2, DUSP4, and DUSP5 [64-66].
While the relative expression of nuclear DUSP1 and DUSP2 was dominant in naive cells, in Thl restimulated cells there was a clear dominance of partners of dephosphorylated ERK, including DUSP2, DUSP4, and DUSP5 in the nucleus, and DUSP6 in the cytoplasm.
Keyse, "Specific inactivation and nuclear anchoring of extracellular signal-regulated kinase 2 by the inducible dual-specificity protein phosphatase DUSP5," Molecular and Cellular Biology, vol.