Reduced Fhit protein expression in nickel-transformed mouse cells and in nickel-induced murine sarcomas
| Autor: | Kazimierz S. Kasprzak, Bhalchandra A. Diwan, Michael P. Waalkes, Robert M. Bare, Renata Kowara, Konstantin Salnikow |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Tumor suppressor gene
Clinical Biochemistry Mice Transgenic Biology medicine.disease_cause Malignant transformation Mice FHIT Nickel medicine Metallothionein Gene silencing Animals Epigenetics neoplasms Molecular Biology Carcinogen Cell Line Transformed Muscle Neoplasms Cell Biology General Medicine Acid Anhydride Hydrolases Neoplasm Proteins Cell Transformation Neoplastic Cancer research Sarcoma Experimental Carcinogenesis |
| Zdroj: | Molecular and cellular biochemistry. 255(1-2) |
| ISSN: | 0300-8177 |
| Popis: | Nickel compounds are carcinogenic and induce malignant transformation of cultured cells. Since nickel has low mutagenic potential, it may act predominantly through epigenetic mechanisms, including down-regulation of tumor suppressor genes. FHIT is a tumor suppressor gene whose expression is frequently reduced or lost in tumors and pre-malignant lesions. Previously, we have shown that the phosphohydrolase activity of Fhit protein, associated with its tumor suppressor action, is inhibited by nickel. In cells, such effect would assist in carcinogenesis. The latter could be further enhanced if nickel also lowered cellular levels of Fhit protein itself, e.g. by down-regulation of FHIT gene. To test this possibility, we determined Fhit protein and Fhit-mRNA levels in a nickel-transformed mouse cell line and in nickel-induced murine sarcomas. In B200 cells, derived by nickel treatment of BALB/c-3T3 cells and exhibiting a malignant phenotype, Fhit protein levels were 50% of those in the parental cells, while Fhit-mRNA expression remained unchanged. A decrease of up to > 90% in Fhit protein levels was also observed in 22 local sarcomas (mostly fibrosarcomas) induced by i.m. injection of nickel subsulfide in C57BL/6 and MT+ (C57BL/6 overexpressing metallothionein) mice, as compared with normal muscles. Moreover, Fhit was absent in 3 out of 10 sarcomas from MT+ mice and in 1 of 12 sarcomas from C57BL/6 mice. The lack of Fhit protein coincided with the absence of the Fhit-mRNA transcript in these tumors. However, in the other tumors, the decreased Fhit levels were not always accompanied by reduced expression of Fhit-mRNA. Thus, the observed lowering of Fhit protein levels is mostly associated with changes in mRNA expression and protein translation or turnover rates, and rarely with a full silencing of the gene itself. Overall, the decline of Fhit in cells or tissues malignantly transformed by nickel may indicate possible involvement of this effect in the mechanisms of nickel carcinogenesis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink