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Horner, James W.

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Horner

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James W.

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Horner, James W.

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2007 - 20102

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Author's Publications: search.filters.isAuthorOfPublication.58a72db6-d9d3-49cb-8f94-da5baa7d4432

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    The Differentiation and Stress Response Factor XBP-1 Drives Multiple Myeloma Pathogenesis
    (Cell Press, 2007) Carrasco, Daniel R.; Sukhdeo, Kumar; Protopopova, Marina; Enos, Miriam; Zheng, Mei; Mani, Mala; Ivanova, Elena V.; Tonon, Giovanni; Sinha, Raktim; Carrasco, Daniel E.; Henderson, Joel; Pinkus, Geraldine; Munshi, Nikhil; Horner, James W.; Protopopov, Alexei; Anderson, Kenneth; DePinho, Ronald A.
    Multiple myeloma (MM) evolves from a highly prevalent premalignant condition termed MGUS. The factors underlying the malignant transformation of MGUS are unknown. We report a MGUS/MM phenotype in transgenic mice with Eμ-directed expression of the XBP-1 spliced isoform (XBP-1s), a factor governing unfolded protein/ER stress response and plasma-cell development. Eμ-XBP-1s elicited elevated serum Ig and skin alterations. With age, Eμ-xbp-1s transgenics develop features diagnostic of human MM, including bone lytic lesions and subendothelial Ig deposition. Furthermore, transcriptional profiles of Eμ-xbp-1s lymphoid and MM cells show aberrant expression of known human MM dysregulated genes. The similarities of this model with the human disease, coupled with documented frequent XBP-1s overexpression in human MM, serve to implicate XBP-1s dysregulation in MM pathogenesis.
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    Somatic p16INK4a Loss Accelerates Melanomagenesis
    (Nature Publishing Group, 2010) Monahan, K B; Rozenberg, G I; Krishnamurthy, J; Johnson, S M; Liu, W; Bradford, M K; Horner, James W.; DePinho, Ronald A.; Sharpless, N E
    Loss of p16\(^{INK4a}–RB\) and ARF–p53 tumor suppressor pathways, as well as activation of RAS–RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16\(^{INK4a}\) are associated with familial melanoma, most melanomas result from somatic genetic events: often p16\(^{INK4a}\) loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16\(^{INK4a}\)-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16\(^{INK4a}\) and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16\(^{INK4a}\) and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.