Biomedical subjects

Nikita Popov

Publications and source records attributed to Nikita Popov.

3 recordsLinked to original sources

PubMed2003

The Mad and Myc basic domains are functionally equivalent.

The Myc/Max/Mad family of transcription factors plays a fundamental role in the regulation of cell proliferation, oncogenic transformation, and cell differentiation. However, it remains unclear whether different heterodimers, such as Myc/Max and Mad/Max, recognize the same or different target genes in vivo. We show by chromatin immunoprecipitation that Myc target genes are also recognized by Mad1 in differentiated HL60 cells. We also substituted the complete basic region of Myc for the corresponding region of Mad. Wild-type c-Myc was then compared with c-Myc(Mad-BR) in oncogenic transformation, regulation of cell proliferation, induction of apoptosis, activation of chromosomal gene expression, and direct binding to chromosomal sites by chromatin immunoprecipitation. We find that the wild-type c-Myc and c-Myc/MadBR proteins have indistinguishable biological activity and target gene recognition in vivo. These data are consistent with a model in which Myc and Mad regulate a common set of target genes.

Amino Acid Sequence↗

PubMed2002

The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase (hTERT) gene in human cells.

Activation of telomerase, essential for cellular immortalization and transformation, requires the induction of its catalytic component, telomerase reverse transcriptase (hTERT). However, biochemical and genetic mechanisms for the control of hTERT expression remain undefined. In the present study, we demonstrate that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) induces hyperacetylation of histones at the hTERT proximal promoter, directly transactivates the hTERT gene in normal human telomerase-negative cells, and upregulates hTERT expression in telomerase-positive tumor cells. Overexpression of HDAC1 leads to repression of the hTERT promoter activity. TSA-mediated activation of the hTERT promoter is abolished by the mutation of Sp1 sites at the proximal promoter, suggesting that the effect of TSA is regulated through Sp1 motifs. We also show a physical interaction of Sp1 with HDAC1 and the presence of HDAC1 at the hTERT promoter region. Moreover, hyperacetylation of histones at the hTERT promoter is associated with the natural up-regulation of hTERT expression that occurs in activated T lymphocytes. Taken together, histone acetylation/deacetylation may be a common underlying feature to hTERT transactivation/repression in human normal and malignant cells.

Acetylation↗

PubMed2002

Repression of in vivo growth of Myc/Ras transformed tumor cells by Mad1.

The Myc/Max/Mad network of transcriptional regulatory proteins plays an essential role in cell proliferation, growth, apoptosis, and differentiation. Whereas Myc proteins affect cell cycle progression positively, Mad proteins are negative regulators of cell proliferation. It has been shown in several in vitro systems that Mad proteins antagonize c-Myc functions. In this report we describe the inhibition of tumor cell outgrowth in vivo by Mad1 expression. Transformed cell lines were generated by co-transfection of c-myc, c-H-ras, and a chimeric mad1ER construct into primary rat embryo cells (MRMad1ER cells). Activation of Mad1 by 4-Hydroxy-Tamoxifen (OHT) resulted in abrogation of telomerase activity, reduced cloning efficiency, and decreased proportion of cells in S phase. Injection of MRMad1ER cells into syngenic rats induced aggressively growing tumors after a short latency period. This tumor growth was inhibited by OHT-treatment of animals, with the extent of inhibition correlating with the amount of OHT injected. No effect of OHT on tumor growth was observed with similarly transformed Myc/Ras cell lines which did not express Mad1ER. These data demonstrate that Mad1 is able to suppress Myc/Ras-mediated transformation under in vivo conditions.

Animals↗