Deletion of DDB1 in Mouse Brain and Lens Leads to p53-Dependent Elimination of Proliferating Cells

Cang, Yong; Zhang, Jianxuan; Nicholas, Sally A.; Bastien, Jayson; Li, Baojie; Zhou, Pengbo; Goff, Stephen P.

doi:10.1016/j.cell.2006.09.045

Cited by 138 publications

(185 citation statements)

References 35 publications

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“…Although highly differentiated, hepatocytes can reenter cell cycle and self-renew in response to loss of liver mass. To analyze the role of DDB1 in hepatocyte proliferation, we generated DDB1 F/F ;Mx1-Cre +/− mice, which harbor homozygous floxed DDB1 alleles (DDB1 F ) (21) and an Mx1-Cre transgene (23). We confirmed a very efficient deletion of DDB1 in DDB1 F/F ;Mx1-Cre +/− mouse liver after one i.p.…”

Section: Ddb1mentioning

confidence: 63%

“…We previously reported that DDB1 is essential for survival of proliferating cells in mouse brain and skin, but dispensable for nondividing cells such as neurons (21,22). Although highly differentiated, hepatocytes can reenter cell cycle and self-renew in response to loss of liver mass.…”

Section: Resultsmentioning

confidence: 99%

“…TUNEL-positive apoptotic cells were detected in regenerating livers but became more abundant in livers repopulated with DDB1-expressing hepatocytes (Fig. 2D), suggesting that DDB1-depleted hepatocytes, unlike DDB1-depleted neuronal and epidermal progenitor cells (21,22), do not undergo immediate apoptotic death but can survive for a very long time, presumably to maintain liver structural integrity and metabolic functions. No tissue necrosis (on histologic examination) or cell senescence (based on senescent β-galactosidase staining) were found during the regenerative process.…”

Section: Ddb1-expressing Hepatocytes Replace Ddb1-deficient Hepatocytesmentioning

confidence: 99%

“…Mouse liver tissues or dissected tumors were collected and processed for histological, immunohistochemical (IHC), immunofluorescence (IF), Southern blot, Western blot, or PCR genotyping analysis, essentially as described previously (21). Five-micrometer paraffin 2N 4N 8N 16N 2N 4N 8N 16N 2N 4N 8N tissue sections were used for all analysis except a few performed on frozen sections as indicated.…”

Section: Methodsmentioning

confidence: 99%

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Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Yamaji

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Etiologic risk factors for hepatocellular carcinoma can be involved in the transformation process by directly targeting intracellular signaling pathways or by indirectly stimulating chronic cycles of hepatocyte destruction and regeneration. However, the contribution of these two routes to hepatocarcinogenesis has not been determined, partly because of the difficulty in distinguishing damaged and regenerated hepatocytes. Here we report that induced deletion of the damaged DNA binding protein 1 (DDB1) abrogates the self-renewing capacity of hepatocytes, resulting in compensatory proliferation of DDB1-expressing hepatocytes. Constitutive stimulation of this regeneration process leads to development of hepatocellular carcinoma, which surprisingly contains no disruption of the DDB1 gene, indicating a cell-nonautonomous role of DDB1 inactivation in tumor initiation. Our results suggest that viruses and hepatoxins may cause liver tumors by simply driving hepatocyte turnover without directly targeting cancer cells. of all primary liver cancers, is the fifth most common cancer and the third leading cause of cancer death worldwide (1). HCC development follows a multistep progression from hepatic dysplasia to neoplasia, with accumulation of somatic mutations and chromosomal alterations (2). Conventionally, these genetic alterations are identified in human liver tumor samples by gene expression profiling, genomic and proteomic analysis, and direct sequencing. Candidate genes are subsequently validated in cell cultures and animals. This methodology has led to the identification of oncogenes and tumor suppressor genes important for liver tumor development, such as those regulating Wnt/β-catenin, p53, EGFR receptor tyrosine kinases, and MET/HGF pathways (3).Alternatively, interactions between host factors and HCC-associated pathogens such as hepatitis B virus (HBV) and hepatitis C virus (HCV) can be investigated to understand early molecular and cellular alterations leading to HCC initiation. HBV encodes a nonstructural regulatory protein, HBx, that is required for HBV replication and implicated in HBV-associated HCC (4). How HBx contributes to hepatocarcinogenesis is unclear, but is believed to involve its myriad target host proteins, one of which is the damaged DNA binding protein 1 (DDB1) (5). DDB1 is the linker protein for the Cullin 4 (Cul4) E3 ubiquitin ligase (6), which regulates ubiquitination and proteasomal degradation of proteins essential for nucleotide excision repair [DDB2 (7) and CSB (8)], cell cycle progression [p21 (9, 10), p27 (11), and Myc (12)], DNA replication [Cdt1 (13) and POLH-1 (14)], and cell growth [c-Jun (15) and TSC2 (16)]. Other substrates of the E3 ligase, including XPC (7), histones H3 and H4 (17), and histone H2A (18), are modified without degradation to facilitate DNA damage repair. Several viral regulatory proteins such as the HIV Vpr protein (19) and the simian virus 5 V protein (20) can hijack the E3 ligase to target undesired host factors and benefit the respective viral life cycle.In this...

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Section: Ddb1mentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Ddb1-expressing Hepatocytes Replace Ddb1-deficient Hepatocytesmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Yamaji

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…For the ablation of DDB1, we used DDB1 flox/flox mouse epithelial fibroblasts in which the floxed DDB1 was acutely deleted by infection of adenoviral-Cre adenovirus (58). In uninfected cells, low UVC doses of 2.2 and 4.4 J/m 2 were sufficient to lead to degradation of p12, which was significantly blocked in the Ade-Cre-infected DDB1 flox/flox mouse epithelial fibroblasts (Fig.…”

Section: Cdt2mentioning

confidence: 99%

A Novel Function of CRL4Cdt2

Zhang

Zhao

Darzynkiewicz

et al. 2013

Journal of Biological Chemistry

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Mouse Rad9b is essential for embryonic development and promotes resistance to DNA damage

Leloup

Hopkins

Wang

et al. 2010

Developmental Dynamics

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RAD9 participates in promoting resistance to DNA damage, cell cycle checkpoint control, DNA repair, apoptosis, embryogenesis, and regulation of transcription. A paralogue of RAD9 (named RAD9B) has been identified. To define the function of mouse Rad9b (Mrad9b), embryonic stem (ES) cells with a targeted gene deletion were constructed and used to generate Mrad9b mutant mice. Mrad9b 2/2 embryos are resorbed after E7.5 while some of the heterozygotes die between E12.5 and a few days after birth. Mrad9b is expressed in embryonic brain and Mrad9b 1/2 embryos exhibit abnormal neural tube closure. Mrad9b 2/2 mouse embryonic fibroblasts are not viable. Mrad9b 2/2 ES cells are more sensitive to gamma rays and mitomycin C than Mrad9b 1/1 controls, but show normal gamma-ray-induced G2/M checkpoint control. There is no evidence of spontaneous genomic instability in Mrad9b 2/2 cells. Our findings thus indicate that Mrad9b is essential for embryonic development and mediates resistance to certain DNA damaging agents.

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Deletion of DDB1 in Mouse Brain and Lens Leads to p53-Dependent Elimination of Proliferating Cells

Cited by 138 publications

References 35 publications

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis

A Novel Function of CRL4Cdt2

Mouse Rad9b is essential for embryonic development and promotes resistance to DNA damage

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