A novel polynucleotide encoding a mammalian bifunctional protein kinaseendoribonuclease referred to herein as hIre1p, is provided. hIre1p is expressed in the endoplasmic reticulum (ER) and upregulates the transcription of genes encoding ER protein chaperones, such as, but not limited to, glucose-related proteins (GRP's). Therapeutic, diagnostic and research methods employing the polynucleotide and protein are also provided.