RBP-J-interacting and tubulin-associated protein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma by activating the p53-Fbxw7 pathway

Haihe Wang; Zhanchun Yang; Chunbo Liu; Shishun Huang; Hongzhi Wang; Yingli Chen; Guofu Chen

doi:10.1016/j.bbrc.2014.10.023

RBP-J-interacting and tubulin-associated protein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma by activating the p53-Fbxw7 pathway

Biochem Biophys Res Commun. 2014 Nov 7;454(1):71-7. doi: 10.1016/j.bbrc.2014.10.023. Epub 2014 Oct 14.

Authors

Haihe Wang¹, Zhanchun Yang², Chunbo Liu¹, Shishun Huang¹, Hongzhi Wang¹, Yingli Chen¹, Guofu Chen³

Affiliations

¹ The Key Laboratory of Molecular Diagnosis in Laboratory Medicine, Department of Pathogenobiology, Daqing Branch of Harbin Medical University, Daqing 163319, China.
² Department of General Surgery of Fifth Clinical Hospital of Harbin Medical University, Daqing 163319, China.
³ Department of General Surgery of Fifth Clinical Hospital of Harbin Medical University, Daqing 163319, China. Electronic address: zhangyanjie3@aliyun.com.

PMID: 25445601
DOI: 10.1016/j.bbrc.2014.10.023

Abstract

Aberrant Notch signaling is observed in human hepatocellular carcinoma (HCC) and has been associated with the modulation of cell growth. However, the role of Notch signaling in HCC and its underlying mechanism remain elusive. RBP-J-interacting and tubulin-associated (RITA) mediates the nuclear export of RBP-J to tubulin fibers and downregulates Notch-mediated transcription. In this study, we found that RITA overexpression increased protein expression of p53 and Fbxw7 and downregulated the expression of cyclin D1, cyclin E, CDK2, Hes-1 and NF-κB p65. These changes led to growth inhibition and induced G0/G1 cell cycle arrest and apoptosis in SMMC7721 and HepG2 cells. Our findings indicate that RITA exerts tumor-suppressive effects in hepatocarcinogenesis through induction of G0/G1 cell cycle arrest and apoptosis and suggest a therapeutic application of RITA in HCC.

Keywords: Apoptosis; Cell cycle arrest; HCC; Notch signaling; RITA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / genetics
Apoptosis / physiology
Basic Helix-Loop-Helix Transcription Factors / metabolism
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology*
Cell Cycle Checkpoints / genetics
Cell Cycle Checkpoints / physiology
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cyclin D1 / metabolism
Cyclin E / metabolism
Cyclin-Dependent Kinase 2 / metabolism
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Down-Regulation
F-Box Proteins / metabolism*
F-Box-WD Repeat-Containing Protein 7
Gene Knockdown Techniques
Hep G2 Cells
Homeodomain Proteins / metabolism
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology*
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
RNA, Small Interfering / genetics
Signal Transduction
Transcription Factor HES-1
Transcription Factor RelA / metabolism
Tubulin / metabolism*
Tumor Suppressor Protein p53 / metabolism*
Tumor Suppressor Proteins / metabolism
Ubiquitin-Protein Ligases / metabolism*
Up-Regulation

Substances

Basic Helix-Loop-Helix Transcription Factors
CCND1 protein, human
Cell Cycle Proteins
Cyclin E
DNA-Binding Proteins
F-Box Proteins
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
Homeodomain Proteins
Immunoglobulin J Recombination Signal Sequence-Binding Protein
Neoplasm Proteins
RBPJ protein, human
RELA protein, human
RNA, Small Interfering
TP53 protein, human
Transcription Factor HES-1
Transcription Factor RelA
Tubulin
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
ZNF331 protein, human
Cyclin D1
HES1 protein, human
Ubiquitin-Protein Ligases
CDK2 protein, human
Cyclin-Dependent Kinase 2