Abstract
MCM7, a member of the miniature chromosome maintenance (MCM) protein family, is crucial for the initiation of DNA replication and proliferation in eukaryotic cells. In this report, we demonstrate that RACK1 regulates cell growth and cell cycle progression in human non-small-cell lung cancer by mediating MCM7 phosphorylation through an MCM7/RACK1/Akt signaling complex. RACK1 functions as a central scaffold that brings Akt into physical proximity with MCM7. Overexpression of RACK1 increases interactions between Akt and MCM7 and promotes Akt-dependent MCM7 phosphorylation, which in turn increases MCM7 binding to chromatin and MCM complex formation. Together, these changes promote DNA replication and cell proliferation. Our findings reveal a novel signaling pathway that regulates growth in non-small cell lung cancer.
Highlights
A heterohexameric complex composed of MCM2-7, which acts as a DNA replication ligase with helicase activity at replication forks, initiates chromosomal duplication, a highly precise event that maintains genome stability [1,2,3,4,5,6]
We demonstrate that Receptor for activated C kinase 1 (RACK1) regulates cell growth and cell cycle progression in human non-small-cell lung cancer by mediating Miniature chromosome maintenance 7 (MCM7) phosphorylation through an MCM7/RACK1/Akt signaling complex
We examined the mechanism by which RACK1 interacts with MCM7
Summary
A heterohexameric complex composed of MCM2-7, which acts as a DNA replication ligase with helicase activity at replication forks, initiates chromosomal duplication, a highly precise event that maintains genome stability [1,2,3,4,5,6]. Numerous studies have demonstrated that MCM7 is a pivotal component of the DNA replication initiation complex in Xenopus and yeast [9,10,11,12]; it serves as a proliferation marker and is correlated with tumorigenesis in several human malignancies, including prostate cancer [13], ovarian cancer [14], endometrial carcinoma [15], oral squamous cell carcinoma [16], esophageal adenocarcinoma [17], colorectal adenocarcinoma [18], and glioblastoma [19]. Activation of Akt, a Ser/ Thr kinase that participates in many cellular processes by facilitating growth factor-mediated cell survival and blocking apoptosis [34], is associated with tumorigenesis in various human cancers. A recent study in NSCLC revealed that P-Thr308, but not P-Ser473, which is widely used as a marker of Akt activity, is the major regulator of Akt protein kinase activity [35]
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