Browsing by Author "Rajarajacholan, Uma Karthika"

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    The ING1a Tumor Suppressor Regulates Endocytosis to Induce Cellular Senescence Via the Rb-E2F Pathway
    (PLoS, 2013-03-05) Rajarajacholan, Uma Karthika; Thalappilly, Subhash; Riabowol, Karl
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    Investigation of the role of ING1a in Cellular Senescence and ING1b in Ribosomal DNA transcription
    (2015-02-03) Rajarajacholan, Uma Karthika; Riabowol, Karl
    The INhibitor of Growth (ING) proteins are type II tumor suppressors that regulate epigenetic state and transcription by functioning as stoichiometric members of histone acetyltransferase and histone deacetylase complexes. Expression of the ING1a isoform increases more than 10-fold during replicative senescence. ING1a overexpression itself induced all features of senescence examined. In this study we have identified and characterized a causal role for endocytosis and signal transduction in inducing senescence-associated phenotypes. ING1a regulated endocytosis through transcriptional activation of endocytic adaptor ITSN2. Inhibition of endocytosis altered growth factor signaling pathways leading to Rb-mediated inhibition of E2F activity, enforcing a senescence phenotype. Overexpression of ITSN2 itself induced senescence-associated characteristics in primary cells. The upstream causal role of endocytosis during senescence induction was further confirmed by ING1a-mediated increase in ITSN2 prior to the appearance of senescence markers and also by induction of senescence-associated phenotypes upon altering the stoichiometry of endocytosis regulators. ING1b isoform is well characterized in terms of regulation of cell growth and tumor suppression. Nucleolar localization of ING1b has been previously reported to be associated with stress-induced apoptosis. In this work we observe that ING1 regulates histone acetylation and the chromatin state of rDNA by recruiting HDAC1. ING1 also regulated recruitment of RNA Pol I- associated transcription factor UBF to rDNA, and affected levels of both rRNA and protein synthesis in cells. A role for ING1-mediated rRNA repression was also observed during PMA-induced differentiation of THP-1 cells. We observed that nucleolar localization of ING1 required its NTS motifs while recruitment of HDAC was dependent on the ING1 unique N-terminal region. Knock down of ING1 increased rRNA transcription and affected cellular proliferation during stress. This study identifies two novel mechanisms by which ING1 exerts its tumor suppressor function, by affecting mitogenic signaling pathways and regulating the major transcription process in cells, and confirms that epigenetic processes play an essential role in these process.