title: LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription.
abstract: BACKGROUND
  Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Treatment options are limited and prophylactic agents are not available. We have previously demonstrated an essential role for CREB-regulating transcriptional coactivators (CRTCs) in HTLV-1 transcription.
  
  
  RESULTS
  In this study we report on the negative regulatory role of LKB1 tumor suppressor and salt-inducible kinases (SIKs) in the activation of HTLV-1 long terminal repeats (LTR) by the oncoprotein Tax. Activation of LKB1 and SIKs effectively blunted Tax activity in a phosphorylation-dependent manner, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function. Activated LKB1 and SIKs associated with Tax and suppressed Tax-induced LTR activation by counteracting CRTCs and CREB. Enforced expression of LKB1 or SIK1 in cells transfected with HTLV-1 molecular clone pX1MT repressed proviral transcription. On the contrary, depletion of LKB1 in pX1MT-transfected cells and in HTLV-1-transformed T cells boosted the expression of Tax. Treatment of HTLV-1 transformed cells with metformin led to LKB1/SIK1 activation, reduction in Tax expression, and inhibition of cell proliferation.
  
  
  CONCLUSIONS
  Our findings revealed a new function of LKB1 and SIKs as negative regulators of HTLV-1 transcription. Pharmaceutical activation of LKB1 and SIKs might be considered as a new strategy in anti-HTLV-1 and anti-ATL therapy.
authors.affiliation: Department of Biochemistry, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Hei-Man Vincent
authors.initials: HM
authors.lastname: Tang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Gao
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chan
authors.forename: Yeung-Tung
authors.initials: YT
authors.lastname: Siu
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Wong
authors.forename: Kin-Hang
authors.initials: KH
authors.lastname: Kok
authors.forename: Yick-Pang
authors.initials: YP
authors.lastname: Ching
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D016356:Gene Products, tax / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D016356:Gene Products, tax; C514970:tax protein, Human T-lymphotrophic virus 1; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases