PML-II regulates ERK and AKT signal activation and IFNα-induced cell death

• Published in: Cell communication and signaling Vol. 19; no. 1; p. 70
• Main Authors: Meng, Xueqiong, Chen, Yixiang, Macip, Salvador, Leppard, Keith
• Format: Journal Article
• Language: English
• Published: England BioMed Central 02.07.2021; BMC
• Subjects: AKT; AKT protein; Antibodies; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptotic signaling; Cell activation; Cell death; Cell Survival - drug effects; Cervical cancer; ERK; Extracellular signal-regulated kinase; Flow cytometry; Gene expression; Gene Expression Regulation - drug effects; HeLa Cells; Humans; IFNα; Interferon-alpha - genetics; Isoforms; Kinases; Liver cancer; MAP Kinase Signaling System - genetics; Multiple myeloma; Neoplasms - genetics; Neoplasms - pathology; Pathogens; PML protein; PML-II; Promyelocytic leukemia protein; Promyelocytic Leukemia Protein - genetics; Protein Isoforms - genetics; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-akt - genetics; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; RNA-Binding Proteins - genetics; Signal transduction; siRNA; TNF-Related Apoptosis-Inducing Ligand - genetics; Tumor suppressor genes; α-Interferon; IFNα; AKT; PML-II; Promyelocytic leukemia protein; Apoptotic signaling; ERK
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-021-00756-5

The requirement of promyelocytic leukaemia protein (PML) in interferon (IFN)-induced cell apoptosis is well-established. 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 IFNα-induced cell death. HeLa cells were transiently depleted of PML-II by siRNA treatment and the response of these cells to treatment with IFNα assessed by molecular assays of mRNA and proteins associated with IFN and apoptosis responses. In HeLa cells, death during IFNα 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 IFNα stimulation and consequently increased resistance to IFNα-induced apoptosis. The positive contribution of PML-II to the expression of various IFNα-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. Video Abstract.