Identification of the hSRBC tumor suppressor gene as a novel transcription target of TNFα in human colon epithelial cells

다국어 초록 (Multilingual Abstract)

hSRBC is a recently identified tumor suppressor located at the chromosomal region 11p15.4. hSRBC expression is frequently downregulated in many types of malignancies including colorectal cancer due to the aberrant promoter CpG sites hypermethylation. The hSRBC activation induces cell cycle arrest and apoptosis by enhancing the protein stability of p53. However, the molecular basis of hSRBC activation and its regulation has been poorly understood. To explore the implication of hSRBC abnormality in colorectal tumorigenesis and the molecular mechanism underlying its tumor suppressive function, the present study tested the possible regulation of hSRBC by TNFα. TNFα regulation of hSRBC expression was examined using semi-quantitative RT-PCR and immunoblot assays. It was found that mRNA expression of hSRBC is strongly activated by TNFα in a dose- and time-associated manner in various human colonic epithelial cells, including HCT15 and HT-29. An immunoblot assay also revealed that hSRBC protein expression is increased following TNFα treatment. TNFα induction of hSRBC was blocked by pretreatment of the cells with the NFkB inhibitor BAY11-7082 or transfection with a dominant negative mutant form of IκB, indicating that TNFα-induced hSRBC expression is mediated via the NFκB pathway. Flow cytometric analysis of sub-G1 phase using hSRBC-nonexpressing HCT15 cells revealed that ectopic expression of hSRBC greatly enhances apoptotic response to TNFα. Collectively, these data strongly suggest that hSRBC might be a novel transcription target of TNFα and play an important role in cellular response to TNFα.

목차 (Table of Contents)

• II. Introduction 1
• II. Materials and Methods 3
• III. Results 7
• IV. Discussion 11
• V. Abstract 15
• VI. References 17