本文采用的英格恩产品: Entranster-H4000

MEKs/ERKs-mediated FBXO1/E2Fs interaction interference modulates G₁/S cell cycle transition and cancer cell proliferation

Ga-Eun Lee  ¹ , Dohyun Jeung  ¹ , Weidong Chen  ¹ , Jiin Byun  ¹ , Joo Young Lee  ¹ , Han Chang Kang  ¹ , Hye Suk Lee  ¹ , Dae Joon Kim  ² , Jin-Sung Choi  ³ , Cheol-Jung Lee  ^{1   4} , Hyun-Jung An  ¹ , Yong-Yeon Cho  ^{5   6}

Affiliations

Affiliations

• ¹ Basic Research Laboratory, BK21-4 th Research Team, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
• ² Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, MBMRF, 1.410, 5300, North L St, McAleen, TX, 78504, USA.
• ³ College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea.
• ⁴ Research Center for Materials Analysis, Korea Basic Science Institute, 169-148, Gwahak-ro, Yuseong-gu, Daejeon, 34133, Republic of Korea.
• ⁵ Basic Research Laboratory, BK21-4 th Research Team, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea. yongyeon@catholic.ac.kr.
• ⁶ College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 420-743, Republic of Korea. yongyeon@catholic.ac.kr.

• PMID: 36607545
• DOI: 10.1007/s12272-023-01426-5

Abstract

E2F 1, 2, and 3a, (refer to as E2Fs) are a subfamily of E2F transcription factor family that play essential roles in cell-cycle progression, DNA replication, DNA repair, apoptosis, and differentiation. Although the transcriptional regulation of E2Fs has focused on pocket protein retinoblastoma protein complex, recent studies indicate that post-translational modification and stability regulation of E2Fs play key roles in diverse cellular processes. In this study, we found that FBXO1, a component of S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) complex, is an E2Fs binding partner. Furthermore, FBXO1 to E2Fs binding induced K48 ubiquitination and subsequent proteasomal degradation of E2Fs. Binding domain analysis indicated that the Arg (R)/Ile (I) and R/Val (V) motifs, which are located in the dimerization domain of E2Fs, of E2F 1 and 3a and E2F2, respectively, acted as degron motifs (DMs) for FBXO1. Notably, RI/AA or RV/AA mutation in the DMs reduced FBXO1-mediated ubiquitination and prolonged the half-lives of E2Fs. Importantly, the stabilities of E2Fs were affected by phosphorylation of threonine residues located near RI and RV residues of DMs. Phosphorylation prediction database analysis and specific inhibitor analysis revealed that MEK/ERK signaling molecules play key roles in FBXO1/E2Fs’ interaction and modulate E2F protein turnover. Moreover, both elevated E2Fs protein levels by knockdown of FBXO1 and decreased E2Fs protein levels by sh-E2F3a delayed G₁/S cell cycle transition, resulting in inhibition of cancer cell proliferation. These results demonstrated that FBXO1-E2Fs axis-mediated precise E2Fs stability regulation plays a key role in cell proliferation via G₁/S cell cycle transition.

Keywords: Cell cycle; E2Fs; FBXO1; Phosphorylation; Proliferation; Stability regulation.