[Back to Issue 1 ToC] [Back to Journal Contents] [Back to Biochemistry (Moscow) Home page]
[View Full Article] [Download Reprint (PDF)]

PTPN11 Knockdown Prevents Changes in the Expression of Genes Controlling Cell Cycle, Chemotherapy Resistance, and Oncogene-Induced Senescence in Human Thyroid Cells Overexpressing BRAF V600E Oncogenic Protein

L. V. Putlyaeva1,2, D. E. Demin1,3, A. N. Uvarova1,4, L. S. Zinevich5, M. M. Prokofjeva1, G. R. Gazizova6, E. I. Shagimardanova6, and A. M. Schwartz1,a*

1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia

2Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia

3Moscow Institute of Physics and Technology, 141701 Dolgoprudnyi, Moscow Region, Russia

4Lomonosov Moscow State University, Faculty of Biology, 119234 Moscow, Russia

5Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia

6Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia

* To whom correspondence should be addressed.

Received September 21, 2019; Revised October 20, 2019; Accepted October 20, 2019
The MAPK (RAS/BRAF/MEK/ERK) signaling pathway is a kinase cascade involved in the regulation of cell proliferation, differentiation, and survival in response to external stimuli. The V600E mutation in the BRAF gene has been detected in various tumors, resulting in a 500-fold increase in BRAF kinase activity. However, monotherapy with selective BRAF V600E inhibitors often leads to reactivation of MAPK signaling cascade and emergence of drug resistance. Therefore, new targets are being developed for the inhibition of components of the aberrantly activated cascade. It was recently discovered that resistance to BRAF V600E inhibitors may be associated with the activity of the tyrosine phosphatase SHP-2 encoded by the PTPN11 gene. In this paper, we analyzed transcriptional effects of PTPN11 gene knockdown and selective suppression of BRAF V600E in a model of thyroid follicular epithelium. We found that the siRNA-mediated knockdown of PTPN11 after vemurafenib treatment prevented an increase in the expression CCNA1 and NOTCH4 genes involved in the formation of drug resistance of tumors. On the other hand, downregulation of PTPN11 expression blocked the transcriptional activation of genes (p21, p15, p16, RB1, and IGFBP7) involved in cell cycle regulation and oncogene-induced senescence in response to BRAF V600E expression. Therefore, it can be assumed that SHP-2 participates not only in emergence of drug resistance in cancer cells, but also in oncogene-induced cell senescence.
KEY WORDS: SHP-2, BRAF V600E, thyroid tumor, oncogene-induced senescence

DOI: 10.1134/S0006297920010101