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

Cell Commun Signal. 2021 Jul 2;19(1):70. doi: 10.1186/s12964-021-00756-5.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: AKT; Apoptotic signaling; ERK; IFNα; PML-II; Promyelocytic leukemia protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics*
  • Cell Survival / drug effects
  • Gene Expression Regulation / drug effects
  • HeLa Cells
  • Humans
  • Interferon-alpha / genetics*
  • MAP Kinase Signaling System / genetics
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Promyelocytic Leukemia Protein / genetics*
  • Protein Isoforms / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • RNA-Binding Proteins / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / genetics

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • IFIT2 protein, human
  • IFNA1 protein, human
  • Interferon-alpha
  • Promyelocytic Leukemia Protein
  • Protein Isoforms
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • PML protein, human
  • Proto-Oncogene Proteins c-akt