Model regulatory networks for proteins that are activated and inhibited in the process of induced granulocyte differentiation

Differentiation therapy with all trans retinoic acid (ATRA) is successfully used for the treatment of acute promyelocytic leukemia (APL). At the same time, the development of the resistance and the differentiation syndrome as a side effect is a reason to explore and examine in greater depth the molecular basis of the differentiation therapy and to search the alternative paradigm of the treatment. By the use of ATRA-treated HL-60 cell line as a model object, we have estimated 76 activated and 101 inhibited proteins by the label-free mass-spectrometric profiling. By applying the bioinformatic approach we have obtained model schemes of regulation of the inhibited and activated proteins whose key molecules turn out to be the histone deacetylase 1 (HDAC1) and the transcriptional corepressor (RNF96) respectively. Both of predicted key molecules have been detected in HL-60 cell line at the proteome level in conjunction with Cdk2, DNA-PKcs, Ubc9 and HMGIY molecules in the model scheme regulating the activated protein cluster and the protein kinase p38 alpha involved in the regulating scheme of the inhibited proteins. The pharmacological targeting of these molecules may have an antiproliferative effect and provide the alternative approach to APL treatment.