The polyubiquitin gene ubiquitin C ( UBC ) is considered a stress protective gene and is upregulated under various stressful conditions, which is probably a consequence of an increased demand for ubiquitin in order to remove toxic misfolded proteins. We previously identified heat shock elements ( HSE s) within the UBC promoter, which are responsible for heat shock factor ( HSF )1‐driven induction of the UBC gene and are activated by proteotoxic stress. Here, we determined the molecular players driving the UBC gene transcriptional response to arsenite treatment, mainly addressing the role of the nuclear factor‐erythroid 2‐related factor 2 (Nrf2)‐mediated antioxidant pathway. Exposure of HeLa cells to arsenite caused a time‐dependent increase of UBC mRNA , while cell viability and proteasome activity were not affected. Nuclear accumulation of HSF 1 and Nrf2 transcription factors was detected upon both arsenite and MG 132 treatment, while HSF 2 nuclear levels increased in MG 132‐treated cells. Notably, si RNA ‐mediated knockdown of Nrf2 did not reduce UBC transcription under either basal or stressful conditions, but significantly impaired the constitutive and inducible expression of well‐known antioxidant response element‐dependent genes. A chromatin immunoprecipitation assay consistently failed to detect Nrf2 binding to the UBC promoter sequence. By contrast, depletion of HSF 1, but not HSF 2, significantly compromised stress‐induced UBC expression. Critically, HSF 1‐mediated UBC trans ‐activation upon arsenite exposure relies on transcription factor binding to previously mapped distal HSE s, as demonstrated to occur under proteasome inhibition. These data highlight HSF 1 as the pivotal transcription factor that translates different stress signals into UBC gene transcriptional induction.