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However, the exact mechanisms by which the multiple isoforms of PML protein participate in this process remain not well-understood. We previously demonstrated that PML isoform II (PML-II) positively regulates induced gene expression during a type I IFN response and evaluate here how PML-II contributes to IFN\u03b1-induced cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>HeLa cells were transiently depleted of PML-II by siRNA treatment and the response of these cells to treatment with IFN\u03b1 assessed by molecular assays of mRNA and proteins associated with IFN and apoptosis responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In HeLa cells, death during IFN\u03b1 stimulation was reduced by prior PML-II depletion. PML-II removal also considerably decreased the induced expression of pro-apoptotic ISGs such as ISG54 (IFIT2), and substantially impaired or prevented expression of PUMA and TRAIL, proteins that are associated with the intrinsic and extrinsic apoptotic pathways respectively. Thirdly, PML-II depletion enhanced ERK and AKT pro-survival signaling activation suggesting that PML-II normally suppresses signaling via these pathways, and that lack of PML-II hence led to greater than normal activation of AKT signaling upon IFN\u03b1 stimulation and consequently increased resistance to IFN\u03b1-induced apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The positive contribution of PML-II to the expression of various IFN\u03b1-induced pro-apoptotic proteins and its inhibition of pro-survival signaling together provide a mechanistic explanation for reduced apoptosis under conditions of PML deficiency and may account for at least part of the role of PML as a tumor suppressor gene.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12964-021-00756-5","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T07:02:46Z","timestamp":1625209366000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["PML-II regulates ERK and AKT signal activation and IFN\u03b1-induced cell death"],"prefix":"10.1186","volume":"19","author":[{"given":"Xueqiong","family":"Meng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Macip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2155-7919","authenticated-orcid":false,"given":"Keith","family":"Leppard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,2]]},"reference":[{"issue":"1","key":"756_CR1","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","volume":"14","author":"LB Ivashkiv","year":"2014","unstructured":"Ivashkiv LB, Donlin LT. 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