Ribonucleotide reductase small subunit p53R2 suppresses MEK–ERK activity by binding to ERK kinase 2

Abstract

The p53-dependent RR small subunit (p53R2) protein, a newly identified member of the ribonucleotide reductase family, plays a key role in the p53-dependent cellular response to DNA. Several recent studies have suggested that p53R2 also plays an important role in suppressing the invasive potential of human cancer cells. However, the cellular mechanism that regulates invasiveness remains largely unknown. In this study, we show that p53R2 interacts with MEK2 (extracellular signal-regulated kinase (ERK) kinase 2-mitogen-activated protein kinase (MAPK) kinase 2), the molecule immediately upstream of ERK in the Ras-Raf-MAPK signaling cascade. In co-immunoprecipitation and immunofluorescence analyses, we found that p53R2 and MEK2 interact physically in cultured mammalian cells, and that the p53R2 segment comprising amino acids 161-206 is critical for this interaction. Moreover, serum-induced phosphorylation of MEK1/2 and ERK1/2 was greatly augmented in human cancer cells expressing small-interfering RNA against p53R2. On the other hand, phosphorylation of MEK1/2 and ERK1/2 in human cancer cells was markedly attenuated by overexpression of p53R2. Furthermore, MEK2 was required for p53R2 knockdown-induced enhancement of the invasive ability and anchorageindependent growth of human lung cancer H1299 cells. Taken together, these findings show that p53R2 negatively modulates serum-induced MEK-ERK activity and inhibits the MEK-ERK-mediated malignancy potential of human cancer cells.

Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration

“…After 24 h, noninvading cells were removed from the upper membrane surface of the insert using a cotton swab. The invading cells on the lower membrane were stained and counted (32). Statistical Analysis-Results are expressed as mean Ϯ S.E.…”

RRM1 *151A>T, RRM1 ‐756T>C, and RRM1 ‐585T>Gis associated with increased susceptibility of lung cancer in Chinese patients

“…Furthermore, it encodes the regulatory subunit of ribonucleotide reductase which was inhibited by gemcitabine metabolites (5′ diphosphate) 18. In a recent study, ribonucleotide reductase might play a key role in suppressing the invasive capacity and anchorage‐independent growth of human lung cancers through the ability of the ribonucleotide reductase small subunit p53R2 to bind ERK kinase 2, thereby suppressing MEK‐ERK activity 19.…”

Clofarabine Has Apoptotic Effect on T47D Breast Cancer Cell Line via P53R2 Gene Expression

“…Deregulated expression of P53R2 has been shown in various cancer types. 20 P53R2 repairs DNA and acts as scavenger of ROS, maintaining cell survival of both cancerous and non-cancerous cells. Also, other studies showed apposite effects and in some cancers elevated P53R2 level can causes cancer progression through exerting resistance to DNA damaging therapies such as clofarabine and radiotherapy.…”

“…12 In addition, P53R2 down-regulates MEK-ERK signal pathway through direct interaction with ERK-Kinase2. 20 MEK-ERK signaling pathway regulates various cellular processes including cell cycle progression and cell survival, thus inhibition of this pathway is another anti-cancer property of P53R2. 21,22 Since the P53R2 is critical molecule in dNTP formation and DNA repair, we hypothesizes that clofarabine might plays a role in apoptosis and cancer therapy by altering the expression levels of P53R2 gene.…”