Hepatitis B virus X protein, and polyploidy in the development of HCC » książka
Hepatitis B virus X protein, and polyploidy in the development of HCC
ISBN-13: 9783639047080 / Angielski / Miękka / 2009 / 144 str.
Hepatitis B Virus (HBV) X protein (pX) is implicated by an unknown mechanism in hepatocellular carcinoma (HCC) development, characterized by increased rate of chromosomal aberrations. Although most patients clear the infection and develop immunity, chronic infection in 5 to 10% infected patients lead to HCC development in the 4th to 5th decade of life. I demonstrate that tetracycline-regulated pX expression induces multipolar spindles and polyploidy (>4N DNA). To understand the mechanism of pX-mediated polyploidy, I investigated whether pX promotes DNA re-replication. Dual-parameter flow cytometry demonstrates pX-dependent BrdU incorporation in cells with >4N DNA. pX also induces expression of replication initiation factors Cdc6 and Cdtl, while suppressing geminin expression, a negative regulator of re-replication. G2- phase synchronized cells exhibit pX-dependent: i) nuclear Cdc6 and Mcm5 colocalization; ii) absence of nuclear geminin; iii) increased BrdU incorporation; iv) ATR activation; v) RAD17 and H2AX phosphorylation; and vi) co-localization of -H2AX with the DNA elongation factor PCNA."
Hepatitis B Virus (HBV) X protein (pX) is implicatedby an unknown mechanism inhepatocellular carcinoma (HCC) development,characterized by increased rate ofchromosomal aberrations. Although most patients clearthe infection and developimmunity, chronic infection in 5 to 10% infectedpatients lead to HCC development inthe 4th to 5th decade of life. I demonstrate thattetracycline-regulated pX expressioninduces multipolar spindles and polyploidy (>4N DNA).To understand the mechanismof pX-mediated polyploidy, I investigated whether pXpromotes DNA re-replication.Dual-parameter flow cytometry demonstratespX-dependent BrdU incorporation in cellswith >4N DNA. pX also induces expression ofreplication initiation factors Cdc6 andCdtl, while suppressing geminin expression, anegative regulator of re-replication. G2-phase synchronized cells exhibit pX-dependent: i)nuclear Cdc6 and Mcm5 colocalization;ii) absence of nuclear geminin; iii) increased BrdUincorporation; iv) ATRactivation; v) RAD17 and H2AX phosphorylation; andvi) co-localization of γ-H2AXwith the DNA elongation factor PCNA.
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