Ras-induced ROS upregulation affecting cell proliferation is connected with cell type-specific alterations of HSF1/SESN3/p21^Cip1/WAF1pathways

Abstract

Oncogenes of the RAS family regulate many of the cell's activities, including proliferation, survival and differentiation. Activating mutations in these genes are common events for many types of cancer. One of the contradictory points concerning the biological significance of Ras activation is its dual effect (pro- or anti-proliferative) on cell reproduction. One of mechanisms by which Ras proteins influence cell growth is a regulation of intracellular level of reactive oxygen species (ROS), second messengers affecting variety of cellular processes including cell proliferation. Recently it was shown that repression of SESN1 and SESN3 genes, whose protein products control regeneration of peroxiredoxins, can play a critical role in Ras-induced ROS upregulation. In the present study we have found that Ras-induced repression of SESN3 expression and ROS upregulation is mediated via the modifications of transcriptional activity of HSF1. Interestingly, mutant Ras overexpression altered the activity of HSF1 in opposite directions in different cell contexts, in particular in human normal fibroblasts and HaCaT immortalized keratinocytes, but these opposite changes caused similar repression of SESN3 expression followed by elevation of ROS content and inhibition of cell proliferation in corresponding cell types. The inhibitory effect on cell proliferation was mediated by upregulation of p21(Cip1/WAF1). Thus, HSF1/SESN3/ROS/p21(Cip1/WAF1)-mediated deceleration of cell growth may contribute to cell defense systems protecting the organism from excessive proliferation of cells that overexpress activated Ras oncoproteins.

Let-7a regulates mammosphere formation capacity through Ras/NF-κB and Ras/MAPK/ERK pathway in breast cancer stem cells

“…[25][26][27] Previous study showed let-7 is complementary to multiple sequences in the 3 0 UTR of human RAS genes, and represses its expression. 28 NF-kB can act as downstream of Ras pathway.…”

Control of Trx1 redox state modulates protection against methyl methanesulfonate-induced DNA damage via stabilization of p21

“…Several studies have indicated that p21 regulation is sensitive to redox status (27,28), but the underlying mechanism is not clear. Mild oxidative stimulation was shown to cause rapid nuclear export and a transient decrease in p21 protein levels (27), while p21 protein levels increased in response to sublethal doses of H 2 O 2 (29,30), inducing G2/M-phase and multi-phase cell cycle arrest in human lung cancer cells (29).…”

E-Cadherin repression increases amount of cancer stem cells in human A549 lung adenocarcinoma and stimulates tumor growth

“…Western blot analysis, total and nuclear protein extract preparation was performed as previously described. 39 Primary antibodies specific to E-cadherin (M126, Takara), vimentin (M0725, Dako), b-catenin (M3539, Dako), a-tubulin (sc-23948, Santa Cruz Biotechnology), histone H3 (9715, Cell Signaling) and Alexa488-conjugated secondary antibodies were used, band detection was performed using variable mode imager Typhoon9410 (GE Healthcare). The quantitation of protein bands was performed using TotalLab v.2.01 software.…”