Dataset Information

TGF-? regulation of gene expression at early and late stages of HPV16-mediated transformation of human keratinocytes.

ABSTRACT: In our in vitro model for HPV16-mediated transformation, HPV16-immortalized human keratinocytes (HKc/HPV16) give rise to differentiation resistant, premalignant cells (HKc/DR). HKc/DR, but not HKc/HPV16, are resistant to growth inhibition by transforming growth factor beta (TGF-?), due to a partial loss of TGF-? receptor type I. We show that TGF-? activates a Smad-responsive reporter construct in HKc/DR to about 50% of the maximum levels of activation observed in HKc/HPV16. To investigate the functional significance of residual TGF-? signaling in HKc/DR, we compared gene expression profiles elicited by TGF-? treatment of HKc/HPV16 and HKc/DR on Agilent 44k human whole genome microarrays. TGF-? altered the expression of cell cycle and MAP kinase pathway genes in HKc/HPV16, but not in HKc/DR. However, epithelial-mesenchymal transition (EMT) responses to TGF-? were comparable in HKc/HPV16 and HKc/DR, indicating that the signaling pathways through which TGF-? elicits growth inhibition diverge from those that induce EMT in HPV16-transformed cells.

SUBMITTER: Kowli S

PROVIDER: S-EPMC3895483 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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TGF-β regulation of gene expression at early and late stages of HPV16-mediated transformation of human keratinocytes.

Kowli Sangeeta S Velidandla Rupa R Creek Kim E KE Pirisi Lucia L

Virology 20130919 1-2

In our in vitro model for HPV16-mediated transformation, HPV16-immortalized human keratinocytes (HKc/HPV16) give rise to differentiation resistant, premalignant cells (HKc/DR). HKc/DR, but not HKc/HPV16, are resistant to growth inhibition by transforming growth factor beta (TGF-β), due to a partial loss of TGF-β receptor type I. We show that TGF-β activates a Smad-responsive reporter construct in HKc/DR to about 50% of the maximum levels of activation observed in HKc/HPV16. To investigate the fu ...[more]

PMID: 24210100

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Project description:BackgroundSkeletal muscle mass can be markedly reduced through a process called atrophy, as a consequence of many diseases or critical physiological and environmental situations. Atrophy is characterised by loss of contractile proteins and reduction of fiber volume. Although in the last decade the molecular aspects underlying muscle atrophy have received increased attention, the fine mechanisms controlling muscle degeneration are still incomplete. In this study we applied meta-analysis on gene expression signatures pertaining to different types of muscle atrophy for the identification of novel key regulatory signals implicated in these degenerative processes.ResultsWe found a general down-regulation of genes involved in energy production and carbohydrate metabolism and up-regulation of genes for protein degradation and catabolism. Six functional pathways occupy central positions in the molecular network obtained by the integration of atrophy transcriptome and molecular interaction data. They are TGF-beta pathway, apoptosis, membrane trafficking/cytoskeleton organization, NFKB pathways, inflammation and reorganization of the extracellular matrix. Protein degradation pathway is evident only in the network specific for muscle short-term response to atrophy. TGF-beta pathway plays a central role with proteins SMAD3/4, MYC, MAX and CDKN1A in the general network, and JUN, MYC, GNB2L1/RACK1 in the short-term muscle response network.ConclusionOur study offers a general overview of the molecular pathways and cellular processes regulating the establishment and maintenance of atrophic state in skeletal muscle, showing also how the different pathways are interconnected. This analysis identifies novel key factors that could be further investigated as potential targets for the development of therapeutic treatments. We suggest that the transcription factors SMAD3/4, GNB2L1/RACK1, MYC, MAX and JUN, whose functions have been extensively studied in tumours but only marginally in muscle, appear instead to play important roles in regulating muscle response to atrophy.

Dataset Information

TGF-? regulation of gene expression at early and late stages of HPV16-mediated transformation of human keratinocytes.

Publications

TGF-β regulation of gene expression at early and late stages of HPV16-mediated transformation of human keratinocytes.

Similar Datasets

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