E2f8 mediates tumor suppression in postnatal liver development

Machiraju, Raghu; Kent, L. N.; Rakijas, J. B.; Pandit, S. K.; Westendorp, B.; Chen, H.; Huntington, J. T.; Tang, X.; Bae, S.; Srivastava, A.; Senapati, S.; Koivisto, C.; Martin, C. K.; Cuitino, M. C.; Perez, M.; Matondo, R. B.

dc.creator	Machiraju, Raghu
dc.creator	Kent, L. N.
dc.creator	Rakijas, J. B.
dc.creator	Pandit, S. K.
dc.creator	Westendorp, B.
dc.creator	Chen, H.
dc.creator	Huntington, J. T.
dc.creator	Tang, X.
dc.creator	Bae, S.
dc.creator	Srivastava, A.
dc.creator	Senapati, S.
dc.creator	Koivisto, C.
dc.creator	Martin, C. K.
dc.creator	Cuitino, M. C.
dc.creator	Perez, M.
dc.creator	Matondo, R. B.
dc.date	2018-10-05T07:34:34Z
dc.date	2018-10-05T07:34:34Z
dc.date	2016-08-01
dc.date.accessioned	2022-10-25T08:51:05Z
dc.date.available	2022-10-25T08:51:05Z
dc.identifier	https://www.jci.org/articles/view/85506
dc.identifier	https://www.suaire.sua.ac.tz/handle/123456789/2608
dc.identifier.uri	http://hdl.handle.net/123456789/91003
dc.description	Endocrinology, 2009, 150 (1): 540-545
dc.description	E2F-mediated transcriptional repression of cell cycle–dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8’s tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8’s DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development
dc.description	NFP grant : R.B.M., DU.282001.1.3
dc.format	application/pdf
dc.publisher	The American Society for Clinical Investigation
dc.subject	Liver
dc.subject	E2f8
dc.subject	Tumor
dc.subject	E2f
dc.subject	HCC
dc.subject	Hepatocyte
dc.title	E2f8 mediates tumor suppression in postnatal liver development
dc.type	Article