Cell cycle checkpoint control: The cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad‑spectrum cancer gene therapy - A review of molecular mechanisms for oncologists

Abstract

Basic research in genetics, biochemistry and cell biology has identified the executive enzymes and protein kinase activities that regulate the cell division cycle of all eukaryotic organisms, thereby elucidating the importance of site-specific protein phosphorylation events that govern cell cycle progression. Research in cancer genomics and virology has provided meaningful links to mammalian checkpoint control elements with the characterization of growth-promoting proto-oncogenes encoding c-Myc, Mdm2, cyclins A, D1 and G1, and opposing tumor suppressor proteins, such as p53, pRb, p16INK4A and p21WAF1, which are commonly dysregulated in cancer. While progress has been made in identifying numerous enzymes and molecular interactions associated with cell cycle checkpoint control, the marked complexity, particularly the functional redundancy, of these cell cycle control enzymes in mammalian systems, presents a major challenge in discerning an optimal locus for therapeutic intervention in the clinical management of cancer. Recent advances in genetic engineering, functional genomics and clinical oncology converged in identifying cyclin G1 (CCNG1 gene) as a pivotal component of a commanding cyclin G1/Mdm2/p53 axis and a strategic locus for re-establishing cell cycle control by means of therapeutic gene transfer. The purpose of the present study is to provide a focused review of cycle checkpoint control as a practicum for clinical oncologists with an interest in applied molecular medicine. The aim is to present a unifying model that: i) clarifies the function of cyclin G1 in establishing proliferative competence, overriding p53 checkpoints and advancing cell cycle progression; ii) is supported by studies of inhibitory microRNAs linking CCNG1 expression to the mechanisms of carcinogenesis and viral subversion; and iii) provides a mechanistic basis for understanding the broad-spectrum anticancer activity and single-agent efficacy observed with dominant-negative cyclin G1, whose cytocidal mechanism of action triggers programmed cell death. Clinically, the utility of companion diagnostics for cyclin G1 pathways is anticipated in the staging, prognosis and treatment of cancers, including the potential for rational combinatorial therapies.

Proteomics Analysis Identified Hub Genes Associated With RNAi-Induced Silencing of G1 Cyclins in MDA-MB-231 Cells

“…Interestingly, the increase in expression of HSP90AA1 and ACTB resulted in the activation of TP53 that suggested their contribution to the survival of tumor cells. It should be noted that this evidence was recently reported [36].…”

Parallel global profiling of plant TOR dynamics reveals a conserved role for LARP1 in translation

“…Human CCNG1, a member of the atypical G-type cyclin family that evolved in animals, is encoded by a core 5′TOP mRNA and is clearly regulated by TOR-LARP1-5′TOP signaling ( Philippe et al, 2020 ). Unlike typical cyclins, CCNG1 is understood to primarily function in coordinating the vertebrate-specific PP2A-Mdm2-p53 pathway that controls stress-responsive cell-cycle arrest ( Bennin et al, 2002 ; Gordon et al, 2018 ; Okamoto et al, 2002 ; Russell et al, 2012 ). Human CCND1 , which encodes a member of the D-type cyclin family that promotes the G1 to S phase cell-cycle transition, is also translationally promoted when TOR is active, but apparently through LARP1-independent mechanisms, including the TOR-4EBP-eIF4E signaling axis ( Averous et al, 2008 ; Musgrove, 2006 ).…”

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

“…Recent studies have identified E3 ubiquitin ligase MDM2 as a novel therapeutic target in cervical cancer, unveiling a great treatment opportunity for cervical cancer patients [4,[19][20][21][22][23]. MDM2, known as Murine double minute 2, is known to be a negative regulator of p53 tumor suppressor gene [22].…”