4.0 Review

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

Journal

MOLECULAR AND CLINICAL ONCOLOGY
Volume 9, Issue 2, Pages 115-134

Publisher

SPANDIDOS PUBL LTD
DOI: 10.3892/mco.2018.1657

Keywords

CCNG1; cyclin-dependent kinase; protein phosphatase 2A; tumor suppressor; p53; Mdm2; proto-oncogene; gene delivery; microRNAs; cancer gene therapy; Rexin-G

Categories

Funding

  1. Sarcoma Oncology Center, USA
  2. DELTA Next-Gen, LLC, USA

Ask authors/readers for more resources

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, p16(INK4A) and p21(WAF1), 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.0
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available