ABSTRACT
Cyclin E1 (CCNE1) gene amplification occurs in approximately 20% of ovarian high grade serous carcinoma (HGSC) and is associated with chemotherapy resistance and, in some studies, overall poor prognosis. The role of cyclin E1 in inducing S phase entry relies upon its interactions with cyclin dependent kinases (CDK), specifically CDK2. Therapies to target cyclin E1-related functions have centered on CDK inhibitors and proteasome inhibitors. While many studies have helped elucidate the functions and regulatory mechanisms of cyclin E1, further research utilizing cyclin E1 as a therapeutic target in ovarian cancer is warranted. This review serves to present the scientific background describing the role and function of cyclin E1 in cancer development and progression, to distinguish cyclin E1-amplified HGSC as a unique subset of ovarian cancer deserving of further therapeutic investigation, and to provide an updated overview on the studies which have utilized cyclin E1 as a target for therapy in ovarian cancer.
Subject(s)
Cyclin E/physiology , Cystadenocarcinoma, Serous/etiology , Oncogene Proteins/physiology , Ovarian Neoplasms/etiology , Cyclin E/antagonists & inhibitors , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/physiology , Cystadenocarcinoma, Serous/therapy , Female , Humans , Oncogene Proteins/antagonists & inhibitors , Ovarian Neoplasms/therapyABSTRACT
We report the cloning and characterization of the alternatively spliced mouse gene zfp162, formerly termed mzfm, the homolog of the human ZFM1 gene encoding the splicing factor SF1 and a putative signal transduction and activation of RNA (STAR) protein. The zfp162 gene is about 14 kb long and consists of 14 exons and 13 introns. Comparison of zfp162 with the genomic sequences of ZFM1/SF1 revealed that the exon-intron structure and exon sequences are well conserved between the genes, whereas the introns differ in length and sequence composition. Using fluorescent in situ hybridization, the zfp162 gene was assigned to chromosome 19, region B. Screening of a genomic library integrated in lambda DASH II resulted in the identification of the 5'-flanking region of zfp162. Sequence analysis of this region showed that zfp162 is a TATA-less gene containing an initiator control element and two CCAAT boxes. The promoter exhibits the following motifs: AP-2, CRE, Ets, GRE, HNF5, MRE, SP-1, TRE, TCF1, and PU.1. The core promoter, from position -331 to -157, contains the motifs CRE, SP-1, MRE, and AP-2, as determined in transfected CHO-K1 cells and IC-21 cells by reporter gene assay using a secreted form of human placental alkaline phosphatase. The occurrence of PU.1/GRE supports the view that the zfp162 gene encodes a protein involved not only in nuclear RNA metabolism, as the human ZFM1/SF1, but also in as yet unknown macrophage-inherent functions.
