Dataset Information

XPO7 is a tumor suppressor regulating p21^CIP1-dependent senescence.

ABSTRACT: Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an impaired induction of the cyclin-dependent kinase inhibitor p21^CIP1 during OIS. Deletion of XPO7 correlates with poorer overall survival in several cancer types. Moreover, depletion of XPO7 alleviated OIS and increased tumor formation in a mouse model of liver cancer. Our results suggest that XPO7 is a novel tumor suppressor that regulates p21^CIP1 expression to control senescence and tumorigenesis.

SUBMITTER: Innes AJ

PROVIDER: S-EPMC7919420 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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XPO7 is a tumor suppressor regulating p21<sup>CIP1</sup>-dependent senescence.

Innes Andrew J AJ Sun Bin B Wagner Verena V Brookes Sharon S McHugh Domhnall D Pombo Joaquim J Porreca Rosa María RM Dharmalingam Gopuraja G Vernia Santiago S Zuber Johannes J Vannier Jean-Baptiste JB García-Escudero Ramón R Gil Jesús J

Genes & development 20210218 5-6

Senescence is a key barrier to neoplastic transformation. To identify senescence regulators relevant to cancer, we screened a genome-wide shRNA library. Here, we describe exportin 7 (XPO7) as a novel regulator of senescence and validate its function in telomere-induced, replicative, and oncogene-induced senescence (OIS). XPO7 is a bidirectional transporter that regulates the nuclear-cytoplasmic shuttling of a broad range of substrates. Depletion of XPO7 results in reduced levels of TCF3 and an i ...[more]

PMID: 33602872

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Project description:Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/paraganglioma tumors. Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of the hypoxia-inducible factor 1α (Hif1α) at normal oxygen tension, a theory referred to as "pseudo-hypoxic drive". Other molecular processes, such as oxidative stress, apoptosis, or chromatin remodeling have been also proposed to play a causative role. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. Moreover, the biological factors that determine the tissue-specificity of these tumors have not been identified. In this work, we made use of the inducible SDHD-ESR mouse, a conditional mutant in the SdhD gene, which encodes the small subunit of MCII, and that acts as a tumor suppressor gene in humans. The analysis of the Hif1α pathway in SDHD-ESR tissues and in two newly derived cell lines after complete SdhD loss -a requirement for hereditary paraganglioma type-1 tumor formation in humans- partially recapitulated the "pseudo-hypoxic" response and rendered inconsistent results. Therefore, we performed microarray analysis of adrenal medulla and kidney in order to identify other early gene expression changes elicited by SdhD deletion. Our results revealed that each mutant tissue displayed different variations in their gene expression profiles affecting to different biological processes. However, we found that the Cdkn1a gene was up-regulated in both tissues. This gene encodes the cyclin-dependent kinase inhibitor p21(WAF1/Cip1), a factor implicated in cell cycle, senescence, and cancer. The two SDHD-ESR cell lines also showed accumulation of this protein. This new and unprecedented evidence for a link between SdhD dysfunction and p21(WAF1/Cip1) will open new avenues for the study of the mechanisms that cause tumors in Sdh mutants. Finally, we discuss the actual role of Hif1α in tumorigenesis.

Dataset Information

XPO7 is a tumor suppressor regulating p21^CIP1-dependent senescence.

Publications

XPO7 is a tumor suppressor regulating p21<sup>CIP1</sup>-dependent senescence.

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Dataset Information

XPO7 is a tumor suppressor regulating p21CIP1-dependent senescence.

Publications

XPO7 is a tumor suppressor regulating p21<sup>CIP1</sup>-dependent senescence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

XPO7 is a tumor suppressor regulating p21^CIP1-dependent senescence.