c-Jun/AP-1 pathway-mediated cyclin D1 expression participates in low dose arsenite-induced transformation in mouse epidermal JB6 Cl41 cells

Abstract

Arsenic is a well-documented human carcinogen associated with skin carcinogenesis. Our previous work reveals that arsenite exposure is able to induce cell transformation in mouse epidermal cell JB6 Cl41 through the activation of ERK, rather than JNK pathway. Our current studies further evaluate downstream pathway in low dose arsenite-induced cell transformation in JB6 Cl41 cells. Our results showed that treatment of cells with low dose arsenite induced activation of c-Jun/AP-1 pathway, and ectopic expression of dominant negative mutant of c-Jun (TAM67) blocked arsenite-induced transformation. Furthermore, our data indicated that cyclin D1 was an important downstream molecule involved in c-Jun/AP-1-mediated cell transformation upon low dose arsenite exposure, because inhibition of cyclin D1 expression by its specific siRNA in the JB6 Cl41 cells resulted in impairment of anchorage-independent growth of cells induced by low dose arsenite. Collectively, our results demonstrate that c-Jun/AP-1-mediated cyclin D1 expression is at least one of the key events implicated in cell transformation upon low dose arsenite exposure.

X-linked Inhibitor of Apoptosis Protein (XIAP) Regulation of Cyclin D1 Protein Expression and Cancer Cell Anchorage-independent Growth via Its E3 Ligase-mediated Protein Phosphatase 2A/c-Jun Axis

“…AP-1 is a canonical regulator of transcription of cyclin D1 (37). Deficiency of XIAP E3 ligase activity repressed AP-1 transcriptional activity (Fig.…”

“…Because previous studies have demonstrated that NFB and AP-1 are two key transcription factors in the mediation of cyclin D1 transcription (23,36,37) and because BIR domains of XIAP have been reported to be crucial for NFB activation (38), cytoplasmic and nuclear extracts were prepared, and the nuclear/cytoplasm distribution of NFB components (p65 and p50) was examined by Western blot in comparison with the distribution of another transcription factor, c-Jun, which is a major component of AP-1, in the transfectants. Consistent with the reported BIR domain regulation of NFB activation (38), our results showed that XIAP deletion or BIR domain deficiency reduced the nuclear/cytoplasm ratio of either p65 or p50 protein levels in comparison with those in WT cells, whereas RING domain deletion did not show this regulatory effect (Fig.…”

Aberrant Cell Proliferation by Enhanced Mitochondrial Biogenesis via mtTFA in Arsenical Skin Cancers

“…32,33 Although cyclin D1 was associated with proliferation by arsenic in human primary keratinocytes, 19 it remains an open question whether cyclin D1 contributed exclusively to the proliferation of keratinocytes. This study indicates that arsenic increases mitochondrial functions and proliferation through up-regulation of mtTFA, which is likely independent of cyclin D1 (Figures 7 and 8).…”

The Chinese Herb Isolate Isorhapontigenin Induces Apoptosis in Human Cancer Cells by Down-regulating Overexpression of Antiapoptotic Protein XIAP

“…The human SP1 fragments were amplified by primers 5Ј-CCAGGCCCTCCAAGC-AGCAC-3Ј and 5Ј-GCTGCTGGTCTGCCCCAAGG-3Ј. The PCR products were separated on 2% agarose gels and stained with ethidium bromide, and the images were visualized and scanned with UV lights with FluorChem SP imaging system (Alpha Innotech Inc.) as described previously (16).…”