Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas

Higashitsuji, Hiroaki; Itoh, Katsuhiko; Nagao, Toshikazu; Dawson, Simon; Nonoguchi, Kohsuke; Kido, Takahiro; Mayer, Roland; Arii, Shigeki; Fujita, Jun

doi:10.1038/71600

Cited by 285 publications

(365 citation statements)

References 18 publications

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“…This study also showed that TBP-1 has tumour-suppressive properties, a finding confirmed subsequently by other groups (Pollice et al, 2007). Several proteins, whose cellular levels are regulated by TBP-1, may be involved in mediating its tumour-suppressive effects, including p14ARF (Pollice et al, 2007), HIF1a (Corn et al, 2003) and Rb (Higashitsuji et al, 2000). Our findings suggest that negative regulation of Fra-1 levels may also contribute to the ability of TBP-1 to act as a tumour suppressor.…”

Section: Discussionsupporting

confidence: 87%

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

et al. 2011

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Fos-related antigen-1 (Fra-1) is a member of the Activator Protein-1 (AP-1) transcription factor superfamily that is overexpressed in a variety of cancers, including colon, breast, lung, bladder and brain. High Fra-1 levels are associated with enhanced cell proliferation, survival, migration and invasion. Despite its frequent overexpression, the molecular mechanisms that regulate the accumulation of Fra-1 proteins in tumour cells are not well understood. Here, we show that turnover of Fra-1, which does not require ubiquitylation, is cooperatively regulated by two distinct mechanisms-association with the 19S proteasomal subunit, TBP-1, and by a C-terminal degron, which acts independently of TBP-1, but is regulated by RAS-ERK (extracellular signal-regulated kinase) signalling. TBP-1 depletion stabilized Fra-1 and further increased its levels in tumour cells expressing RAS-ERK pathway oncogenes. These effects correlated with increased AP-1 transcriptional activity. We suggest that during Fra-1 degradation, association with TBP-1 provides a mechanism for ubiquitin-independent proteasomal recognition, while the C terminus of the protein regulates its subsequent proteolytic processing.

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Section: Discussionsupporting

confidence: 87%

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

et al. 2011

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“…Somatic inactivating mutations and homozygous deletions of the gene are rarely observed in HCC (Biden et al, 1997;Jin et al, 2000). Finally, Gankyrin was found to be overexpressed in all cases of 34 analysed HCC (Higashitsuji et al, 2000). Moreover, the authors found that Gankyrin induced anchorage-independent growth and tumorigenicity in NIH/3T3 cells.…”

Section: )mentioning

confidence: 92%

Genetics of hepatocellular tumors

2006

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Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1a (HNF1a) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/b-catenin pathway through CTNNB1/b-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently b-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.

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“…36 In addition, PSMD10/ Gankyrin, a subunit of the 26S proteasome that accelerates the degradation of retinoblastoma, is overexpressed in HCC. 37 Also, enhanced activation of ubiquitin-dependent protein degradation may account for deregulation of cell cycle control and faster cell prolifera- tion in the poor survival group (subclass A). Therefore, deregulated components in ubiquitin-mediated protein degradation may provide attractive therapeutic targets for novel HCC treatment modalities.…”

Section: Discussionmentioning

confidence: 99%

Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling

et al. 2004

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We analyzed global gene expression patterns of 91 human hepatocellular carcinomas (HCCs) to define the molecular characteristics of the tumors and to test the prognostic value of the expression profiles. Unsupervised classification methods revealed two distinctive subclasses of HCC that are highly associated with patient survival. This association was validated via 5 independent supervised learning methods. We also identified the genes most strongly associated with survival by using the Cox proportional hazards survival analysis. This approach identified a limited number of genes that accurately predicted the length of survival and provides new molecular insight into the pathogenesis of HCC. Tumors from the low survival subclass have strong cell proliferation and antiapoptosis gene expression signatures. In addition, the low survival subclass displayed higher expression of genes involved in ubiquitination and histone modification, suggesting an etiological involvement of these processes in accelerating the progression of HCC. In conclusion, the biological differences identified in the HCC subclasses should provide an attractive source for the development of therapeutic targets (e.g., HIF1a) for selective treatment of HCC patients. H epatocellular carcinoma (HCC) is the fifth most common cancer in the world, accounting for an estimated 500,000 deaths annually. 1 Although HCC is prevalent in Southeast Asia and sub-Sahara Africa, the incidence of HCC has doubled in the United States over the past 25 years, and incidence and mortality rates are likely to double over the next 10 -20 years. 2 Although much is known about both the cellular changes that lead to HCC and the etiological agents responsible for the majority of HCC cases (hepatitis B virus, hepatitis C virus, alcohol), the molecular pathogenesis of HCC is not well understood. 3 Considerable efforts have been devoted to establishing a prognostic model for HCC by using clinical information and pathological classification to provide information at diagnosis on both survival and treatment options. 4 -10 Although much progress has been made (reviewed by Llovet et al. 11 ), many issues still remain unresolved. For example, a staging system that reliably separates patients with early HCC as well as intermediate to advanced HCC into homogeneous groups with respect to prognosis does not exist. This is particularly important because the natural course of early HCC is unknown and the natural progression of intermediate and advanced HCC are known to be quite heterogeneous. 12 It therefore appears axiomatic that improving the classification of HCC patients into groups with homogeneous prognosis would at least improve the application of currently available treatment modalities and at best provide new treatment strategies.Recently, microarray technologies have been successfully used to predict clinical outcome and survival as well as classify different types of cancer. [13][14][15]

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Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas

Cited by 285 publications

References 18 publications

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

Genetics of hepatocellular tumors

Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling

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