title: Paradoxical effects of a stress signal on pro- and anti-apoptotic machinery in HTLV-1 Tax expressing cells.
abstract: Adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) are associated with Human T-cell lymphotropic virus type 1 (HTLV-1) infection. The viral transactivator, Tax is able to mediate the cell cycle progression by targeting key regulators of the cell cycle such as p21/waf1, p16/ink4a, p53, cyclins D1-3/cdk complexes, and the mitotic spindle checkpoint MAD apparatus, thereby deregulating cellular DNA damage and checkpoint control. Genome expression profiling of infected cells exemplified by the development of DNA microarrays represents a major advance in genome-wide functional analysis. Utilizing cDNA microarray analysis, we have observed an apparent opposing and paradoxical regulatory network of host cell gene expression upon the introduction of DNA damage stress signal. We find the apparent induction of cell cycle inhibitors, and pro- as well as anti-apoptotic gene expression is directly linked to whether cells are at either G1, S, or G2/M phases of the cell cycle. Specifically, a G1/S block is induced by p21/waf1 and p16/ink4a, while pro-apoptotic expression at S, and G2/M is associated with caspase activation, and anti-apoptotic gene expression is associated with up regulation of Bcl-2 family member, namely bfl-1 gene. Therefore, the microarray results indicating expression of both pro- and anti-apoptotic genes could easily be explained by the particular stage of the cell cycle. Mechanism and the functional outcome of induction for both pathways are discussed.
authors.affiliation: Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, NJ, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: de la Fuente
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.forename: Dai
authors.initials: D
authors.lastname: Wang
authors.forename: Longwen
authors.initials: L
authors.lastname: Deng
authors.forename: Kaili
authors.initials: K
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: L Dana
authors.initials: LD
authors.lastname: Stein
authors.forename: Thomas
authors.initials: T
authors.lastname: Denny
authors.forename: Frederick
authors.initials: F
authors.lastname: Coffman
authors.forename: Kylene
authors.initials: K
authors.lastname: Kehn
authors.forename: Shanese
authors.initials: S
authors.lastname: Baylor
authors.forename: Anil
authors.initials: A
authors.lastname: Maddukuri
authors.forename: Anne
authors.initials: A
authors.lastname: Pumfery
authors.forename: Fatah
authors.initials: F
authors.lastname: Kashanchi
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D004789:Enzyme Activation; D005720:Gamma Rays; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism; D008938:Mitosis; D008954:Models, Biological; D009154:Mutation; D015398:Signal Transduction; D013312:Stress, Physiological; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D016356:Gene Products, tax