the accepted model, doubts have been raised over its validity. It has been argued that the genetic and structural evidence supporting the model simply shows BiP dissociation to be merely correlated with Ire1 activation, rather than specifically causing it. An alternative model has been proposed, whereby unfolded proteins interact directly with the ER-lumenal domain of Ire1, causing oligomerization and transautophosphorylation. However these models are not mutually exclusive, it is also possible that both direct interaction of Ire1 with unfolded proteins and dissosiation of BiP from IRE1 contribute to the activation of the Ire1 pathway. Functions The initial phases of UPR activation have two key roles: Translation Attenuation and Cell Cycle Arrest by the PERK Receptor This occurs within minutes to hours of UPR activation to prevent further translational loading of the ER. PERK (protein kinase RNA-like endoplasmic reticulum kinase) activates itself by oligomerization and autophosphorylation of the free luminal domain. The activated cytosolic domain causes translational attenuation by directly phosphorylating the α subunit of the regulating initiator of the mRNA translation machinery, eIF2. This also produces translational attenuation of the protein machinery involved in running the cell cycle, producing cell cycle arrest in the G1 phase. PERK deficiency may have a significant impact on physiological states associated with ER stress. Increased Production of Proteins Involved in the Functions of the UPR UPR activation also results in upregulation of proteins involved in chaperoning malfolding proteins, protein folding and ERAD, including further production of Grp78. Ultimately this increases the cell's molecular mechanisms by which it can deal with the misfolded protein load. These receptor proteins have been identified as: Inositol-requiring kinase 1, whose free luminal domain activates itself by homodimerisation and transautophosphorylation. The activated domain is able to activate the transcription factor XBP1(Xbox binding protein) mRNA (the mammalian equivalent of the yeast Hac1 mRNA) by cleavage and removal of a 26bp intron. The activated transcription factor upregulates UPR 'stress genes' by directly binding to stress element promoters in the nucleus. ATF6 (activating transcription factor 6) is a basic leucine zipper transcription factor. Upon Grp78 dissociation, the entire 90kDa protein translocates to the Golgi, where it is cleaved by proteases to form an active 50kDa transcription factor that translocates to the nucleus. It binds to stress element promoters upstream of genes that are upregulated in the UPR. The aim of these responses is to remove the accumulated protein load whilst preventing any further