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MicroRNAs control cellular processes by regulating expression of their target genes. Here we report that neuro-epithelial transforming gene 1 (NET1) is a target of tumor suppressor microRNA 22 (miR-22). miR-22 is downregulated in peripheral blood mononuclear cells derived from chronic myeloid leukemia (CML) patients and in CML cell line K562. NET1 was identified as one of the targets of miR-22 using both in vitro and in vivo experiments. Either mutations or naturally occurring single-nucleotide polymorphisms in NET1 3 0 -UTR that map at the miR-22 binding site were found to affect binding of miR-22 to NET1 mRNA. Over expression of NET1 in K562 cells resulted in increased proliferation. However decreased proliferation and alteration in cell cycle were observed on either overexpression of miR-22 or knockdown of NET1 expression respectively. We also found that overexpression of miR-22 or NET1 knockdown inhibits actin fiber formation, probably by downregulation of NET1 as NET1 knockdown also resulted in depletion of actin fiber formation. We suggest that the oncogenic properties of CML cells are probably due to deregulated expression of NET1 as a result of altered expression of miR-22.

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Increased lignolytic peroxidase activity has been demonstrated with the addition of sublethal doses of toxic H2O2 in Streptomyces viridosporus T7A. Until now, the effect of H2O2 at the molecular level has not been well characterized. Here, for the first time we report the isolation and analysis of three peroxide-induced gene homologs from S. viridosporus T7A; ahpC and ahpX (encoding alkyl hydroxyperoxidase subunits) and oxyR (encoding oxygen stress regulatory protein). The genome organization of these stress related genes were found to be divergently adjacent to each other. The protein sequence analysis of the oxyR homolog revealed a helix-turn-helix DNA-binding motif characteristic to the LysR of regulatory proteins induced by H2O2. The nucleotide sequence analysis of the intergenic region between ahpC and oxyR revealed that they shared a core T-n11-A, a signature protein-binding region of LysR family members. Based on similarities in sequence analysis, genetic organization, and the induction of lignin peroxidase activity upon exposure to hydrogen peroxide, we hypothesize a peroxide induction mechanism for the regulation of oxidative lignin biodegradation by S. viridosporus, possibly via use of OxyR which is also involved in regulating the peroxide stress response in this actinomycete.

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Introduction GRP78 overexpression has been associated with bortezomib resistance in multiple myeloma (MM) cells. However, serum GRP78 as a maker of bortezomib based treatment response remains unexplored. The objective of the study was to evaluate serum GRP78 levels in MM patients who underwent bortezomib based induction regimen. Methods After ethical approval, this cross‐sectional study was done in adult MM patients who had completed at least 4 cycles of bortezomib based induction therapy. They were classified into responders (complete response (CR), very good partial response (VGPR), partial response (PR)) and non‐responders (stable disease (SD) and progressive disease (PD)). Thirty healthy volunteers and twenty newly diagnosed multiple myeloma patients were also recruited to identify the disease associated change in GRP78 levels. Serum GRP78 was estimated by ELISA. Surface and intracellular expression of GRP78 in bone marrow plasma cells was evaluated in a subset of MM patients by flowcytometry. Results Thirty MM patients who completed at least 4 cycles of bortezomib based induction therapy [median(range): 52 (38–68) years; Male:20] were enrolled. Out of 30 patients, 20 were responders and 10 were non‐responders. They were comparable at baseline in all clinical and laboratory parameters except serum M protein which was significantly higher in non‐responders (p=0.04). Serum GRP78 levels were not significantly different between responders [median (IQR): 5.2 (3.1,8.0) μg/ml] and non‐responders [median (IQR): 4.3 (0.1,7.1) μg/ml] (p=0.356). Although non‐significant (p=0.342), median serum GRP78 was higher in newly diagnosed patients when compared to healthy volunteers. Bone marrow plasma cell percentage ranged between 0.2 to 57.8% in the analyzed samples. Intracellular GRP78 expression was found to be higher (1.6 to 5 times) when compared to surface expression in plasma cells as well as in malignant subset of plasma cells. Conclusion Serum GRP78 did not differ between responders from non‐responders in MM patients who underwent bortezomib based induction regimen. Support or Funding Information Intramural Research Grant