CIP1-interacting Zinc Finger Protein 1 Research Articles

Identification of DHX9 as a cell cycle regulated nucleolar recruitment factor for CIZ1

CIP1-interacting zinc finger protein 1 (CIZ1) is a nuclear matrix associated protein that facilitates a number of nuclear functions including initiation of DNA replication, epigenetic maintenance and associates with the inactive X-chromosome. Here, to gain more insight into the protein networks that underpin this diverse functionality, molecular panning and mass spectrometry are used to identify protein interaction partners of CIZ1, and CIZ1 replication domain (CIZ1-RD). STRING analysis of CIZ1 interaction partners identified 2 functional clusters: ribosomal subunits and nucleolar proteins including the DEAD box helicases, DHX9, DDX5 and DDX17. DHX9 shares common functions with CIZ1, including interaction with XIST long-non-coding RNA, epigenetic maintenance and regulation of DNA replication. Functional characterisation of the CIZ1-DHX9 complex showed that CIZ1-DHX9 interact in vitro and dynamically colocalise within the nucleolus from early to mid S-phase. CIZ1-DHX9 nucleolar colocalisation is dependent upon RNA polymerase I activity and is abolished by depletion of DHX9. In addition, depletion of DHX9 reduced cell cycle progression from G1 to S-phase in mouse fibroblasts. The data suggest that DHX9-CIZ1 are required for efficient cell cycle progression at the G1/S transition and that nucleolar recruitment is integral to their mechanism of action.

CIZ1 Expression Is Upregulated in Hemangioma of the Tongue.

Hemangioma is a vascular neoplasm and one of the most common benign tumors. The pathogenesis of hemangioma has not been fully understood. CIZ1 (Cip1-interacting zinc finger protein 1) is a nuclear protein and the binding partner of p21. Dysregulation of CIZ1 expression has been reported in various types of cancerous tissues. In this study, we examined CIZ1 expression in hemangioma of the tongue and explored its function in vascular endothelial cells, the proliferative cell type in hemangioma. Immunohistochemistry showed that CIZ1 was highly expressed in hemangioma of the tongue while its expression is minimal in the normal tongue tissues. In vitro, knockdown of CIZ1 expression by shRNA transfection significantly reduced the proliferation and migration of human umbilical vein endothelium cells (HUVECs), suggesting a positive role of CIZ1 in endothelial cell proliferation and migration. Therefore, CIZ1 might involve in pathogenesis of hemangioma of the tongue by regulation of endothelial cell functions.

The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory

The nuclear matrix protein Cip1-interacting zinc finger protein 1 (CIZ1) promotes DNA replication in association with cyclins and has been linked to adult and pediatric cancers. Here we show that CIZ1 is highly enriched on the inactive X chromosome (Xi) in mouse and human female cells and is retained by interaction with the RNA-dependent nuclear matrix. CIZ1 is recruited to Xi in response to expression of X inactive-specific transcript (Xist) RNA during the earliest stages of X inactivation in embryonic stem cells and is dependent on the C-terminal nuclear matrix anchor domain of CIZ1 and the E repeats of Xist CIZ1-null mice, although viable, display fully penetrant female-specific lymphoproliferative disorder. Interestingly, in mouse embryonic fibroblast cells derived from CIZ1-null embryos, Xist RNA localization is disrupted, being highly dispersed through the nucleoplasm rather than focal. Focal localization is reinstated following re-expression of CIZ1. Focal localization of Xist RNA is also disrupted in activated B and T cells isolated from CIZ1-null animals, suggesting a possible explanation for female-specific lymphoproliferative disorder. Together, these findings suggest that CIZ1 has an essential role in anchoring Xist to the nuclear matrix in specific somatic lineages.

CIZ1 is upregulated in hepatocellular carcinoma and promotes the growth and migration of the cancer cells.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, and the prognosis for the HCC remains very poor. Although dys-regulation of CIZ1 (Cip1 interacting zinc finger protein 1) has been observed in various cancer types, its expression and functions in HCC remain unknown. In this study, the mRNA level of CIZ1 in the HCC tissues were examined using real-time polymerase chain reaction, and the effects of CIZ1 on the growth, migration, and metastasis of HCC cells were examined by crystal violet assay, Boyden chamber assay, and in vivo image system, respectively. In addition, the molecular mechanisms were investigated by luciferase assay. Upregulation of CIZ1 in the clinical HCC samples was observed. Forced expression of CIZ1 promoted the growth and migration of HCC cells, while knocking down the expression of CIZ1 inhibited the growth, migration, and metastasis of HCC cells. Molecular mechanism studies revealed that CIZ1 activated YAP/TAZ signaling in HCC cells. Taken together, our study demonstrated the oncogenic roles of CIZ1 in HCC cells and CIZ1 might be a promising therapeutic target for HCC.

CIZ1 promoted the growth and migration of gallbladder cancer cells.

Gallbladder cancer (GBC) is one of the most common and aggressive diseases among the gastrointestinal tract malignancies, and the molecular mechanism underlying this disease remains largely unknown. CIZ1 (Cip1 interacting zinc finger protein 1), a binding partner of p21(Cip1/Waf1), has been found to be involved in the tumorigenesis recently. However, the expression pattern and biological functions of CIZ1 in the progression of GBC are not fully understood. In this study, it was found that the expression of CIZ1 was significantly elevated in GBC samples compared to their adjacent normal tissues. Moreover, overexpression of CIZ1 promoted the growth and migration of GBC cells, while knocking down the expression of CIZ1 inhibited the growth, migration, and tumorigenesis of GBC cells in vitro and in vivo. Mechanistically, CIZ1 was found to interact with TCF4 (T-cell factor) and activate beta-catenin/TCF signaling. Our study demonstrated that CIZ1 played an oncogenic role in the progression of GBC and CIZ1 might be a promising target for the treatment of GBC.

Ciz1 is a novel predictor of survival in human colon cancer

Cip1-interacting zinc-finger protein1 (Ciz1) is a nuclear matrix protein associated DNA replication factor which has been implicated in breast and lung cancer progression. However, the clinical significance of Ciz1 expression in colon cancer has not been determined. This study aimed to examine Ciz1 expression pattern and its potential as a biomarker of prognosis in colon cancer. Using quantitative PCR, tissue microarray (TMA), and ELISA, we evaluated Ciz1 mRNA and protein levels in tumor tissues from patients with colon cancer and in paired adjacent normal tissues. Ciz1 mRNA expression was significantly upregulated in 22 of 39 paired samples (P < 0.001). Immunohistochemistry on TMA-containing samples from 203 colon cancer patients indicated that Ciz1 protein expression was significantly higher in tumor tissues than in adjacent normal tissues (Stuart-Maxwell test, P < 0.001). Elevated expression of Ciz1 protein was significantly correlated with T stage (P < 0.001), N stage (P = 0.005), M stage (P = 0.021), and AJCC stage (P = 0.002). Multivariate Cox proportion hazard model analysis revealed that Ciz1 expression is an independent prognostic factor for overall time (OS; hazard ratio (HR): 1.76; 95% confidence interval (CI): 1.04-2.98; P = 0.034) and disease-free survival (DFS; HR: 2.02; 95% CI: 1.14-3.58; P = 0.017) of patients with colon cancer after colectomy. Our data suggested that Ciz1 may be involved in colon cancer progression and could serve as a novel predictor of survival for colon cancer patients.

CIZ1 regulates the proliferation, cycle distribution and colony formation of RKO human colorectal cancer cells

Cip1-interacting zinc finger protein 1 (CIZ1) is a nuclear protein that was observed to bind to p21Cip1/Waf1. p21Cip1/Waf1 regulates the cell cycle and is associated with colorectal cancer (CRC) progression. However, the effect of CIZ1 on CRC cells remains unclear. In the present study, CIZ1 was observed to be highly expressed in RKO human CRC cells. Silencing of CIZ1 using small interfering RNA (siRNA) suppressed RKO cell proliferation. Flow cytometric analysis demonstrated that knockdown of CIZ1 decreased the percentage of cells in the S phase and increased the ratio of cells in the G0/G1 phase in parallel with upregulated cell apoptosis. Moreover, the number and size of RKO cell colonies was repressed by knockdown of the CIZ1 gene. These results suggested that CIZ1 may be involved in colon cancer progression by regulating cell proliferation, cell cycle, apoptosis and colony formation. Furthermore, CIZ1‑siRNA may provide a novel tool for CRC investigation and therapy.

Research progress and diagnostic strategy of genetic pathogenesis of dystonia

Dystonia is a syndrome of abnormal involuntary movements that are repetitive, twisting or patterned, and can result in abnormal postures. Genetic factors play an important role in the pathogenesis of dystonia. To date, at least 20 dystonic syndromes have been distinguished on a genetic basis ( DYT1-21 , except DYT14 ), 10 of which have had clear causing genes. Recently, major discoveries have appeared in the genetic field: mutations in the transcription factor THAP1 and DNA replication factor CIP1-interacting zinc finger protein 1 ( CIZ1 ) have been linked to adult-onset primary dystonia; proline-rich transmembrane protein 2 ( PRRT2 ) has been tied to paroxysmal kinesigenic dyskinesia; DYT14 has been redefined as DYT5 due to a deletion mutation in guanosine triphosphate cyclohydrolase 1 ( GCH1 ). In addition, the existing diagnostic algorithms for dystonic syndromes rely on the clinicians' experience, without a streamlined diagnostic pathway. Non-specialist clinicians and neurologists may, therefore, find diagnosis of dystonic syndromes difficult. This review focuses on the molecular and phenotypic features of the hereditary dystonias, with emphasis on recent advances. Also an eight-question approach is proposed in this review to inform specialists and general neurologists on the appropriate diagnostic test for each patient with a possible dystonic syndrome.