we found that hela cells overexpressing nuclear importin 2 exhibited downregulation of transcripts encoded by 62  genes , including 22 encoding replication - dependent histones , as well as selective upregulation of only two transcripts , including serine / threonine kinase 35 ( stk35 ) . the contrast between the large numbers of downregulated mrnas with the small number identified as upregulated suggested to us that importin 2 can effectively suppress gene expression through chromatin binding . we hypothesize that this occurs through importin  interaction with the cnlss in karyophilic proteins such as transcription factors , since the cnls has been shown to overlap with dna binding regions in some cargo proteins . thus we predict that , in circumstances when importin  accumulates in the nucleus , certain transcription factors interact with importin  via their cnls and this binding compromises or changes their transcriptional activities . because the apparent numerical difference between the number of up- and downregulated genes suggests that nuclear importin  generally acts as a suppressor for transcription factors , and in case of stk35 , it operates by suppressing the activity of some protein that inhibits transcription . in support of this , we found that the region  1 kbp upstream of the first exon of stk35 served a repressor function for the core promoter . these data suggest that importin  inhibits the suppressor for the stk35 core promoter , resulting in its enhanced activity . the physiological significance of changes of nucleocytoplasmic transport under stress conditions has been linked to perturbed protein shuttling within signaling cascades , structural modifications of transport machinery , including the nuclear pore complex ( npc ) , and evocation of cell death by apoptosis . however , there is relatively little discussion about the mechanisms by which changes in cellular metabolism arising from stress , its associated alterations in nucleocytoplasmic transport , and the subsequent impact on cell fate . we previously reported that intracellular atp levels decreased following exposure to all tested stresses : uv - irradiation , heat shock and hydrogen peroxide , and this caused the ran gradient to collapse . this finding is in agreement with a previous report that cellular atp depletion following exposure to 2-deoxyglucose and sodium azide leads to a decrease in free rangtp which is followed by nuclear accumulation of importin . depletion of cellular atps itself has been known to induce necrosis or caspase - independent cell death , but not apoptosis , because of the high levels of atp required for caspase activation . in addition , apoptosis requires active nuclear transport mediated by importin  and is dependent upon a ran gradient and intact npcs . thus several observations support our hypothesis that blocking the classical nuclear transport pathway , including by induced nuclear accumulation of importin  under conditions of atp depletion , results in the inhibition of apoptosis and promotion of non - apoptotic cell death . taken together with the ability of stk35 to enhance caspase - independent cell death under oxidative stress , it becomes evident that the combined outcomes of both deficient classical nuclear transport and transcriptional modulation by nuclear - localized importin  direct cell fate toward a cell death pathway that bypasses apoptosis , such as necrosis , upon stress exposure . these findings reveal a new mechanistic approach to understanding how non - apoptotic cell death is elicited by a decrease in intracellular atp in cells under stress , through the re - distribution of importin  into the nucleus ( fig .  1 ) . schematic model for mode of cell death induced by stress in response to depleted intracellular atp . cellular stresses which deplete intracellular atp induce a ran gradient collapse and importin  accumulates in the nucleus . this leads to a block in classical nucleocytoplasmic protein transport via the importin /1 pathway . nuclear importin  functions to elevate stk35 transcription and promotes non - apoptotic cell death in oxidative stress . the ran gradient collapse may be induced by both atp depletion and through modulated activity of ran - related proteins , such as rcc1 , in some stress conditions . is the nuclear accumulation of importin  restricted to stress conditions ? c. elegans importin  proteins , particularly ima-1 and -2 , were detected in the nucleoplasm of germ cells . in drosophila , all three importin s exhibit nuclear accumulation in a stage - specific manner during spermatogenesis . in mammals , importin 4 , but not its close subfamily member importin 3 , is predominantly nuclear in the adult testis , with a striking nuclear signal evident in pachytene spermatocytes and round spermatids . in addition , the importin 4 protein exhibits nuclear localization in the murine embryonic stem ( mes ) cells in undifferentiated , but not differentiated , stages . these observations suggest that nuclear - localized importin  proteins serve key roles in cell fate choice between maintenance of pluripotency and differentiation . recently , a novel importin  family member was identified , referred to as karyopherin 7 ( kpna7 ) in human , mouse and cattle . kpna7 is closely related to importin 2 and localized in the nucleus in mouse oocytes and zygotes as well as in hela cells . interestingly , a mutant kpna7 gene caused abnormal expression of chromatin modification - associated genes and also induced epigenetic modification of histone h3k27me3 . these observations bear a striking correlation to our finding that nuclear importin 2 causes downregulation of mrnas encoding replication - dependent histones and highlight the need to gain a precise understanding of the genomic and chromatin - associated modifications effected by nuclear importin  in the nucleus . of direct relevance to human disease , breast cancer cells exhibit the remarkable expression and nuclear localization of human karyopherin 2 ( kpna2 , ortholog of mouse importin 2 ) , and this may be significantly associated with patient survival rates . high expression and nuclear localization of kpna2 was also observed in lung tumor tissues , esophageal squamous cell carcinoma , bladder cancer and prostate cancer . moreover , increased expression and elevated nuclear accumulation of importin 5 and importin 7 have been reported in tubular and glomerular cells of diabetic rats . collectively these reports highlight the potential contribution of nuclear importin  to various cellular events , each of which might involve a different substrate specificity , reflect cell - specific expression patterns and effect distinct transcriptional outcomes . our findings should encourage investigations of additional functions for importin  in a variety of cellular states and fates .