Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer

DiCiommo, David P.; Gallie, Brenda L.; Bremner, Rod

doi:10.1006/scbi.2000.0326

Cited by 115 publications

(91 citation statements)

References 162 publications

(170 reference statements)

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“…RB is expressed ubiquitously in mammals, and it is believed that RB function must be compromised for a cancer to develop (Weinberg, 1995). This often occurs through mutation of the RB gene, as is found in retinoblastomas (DiCiommo et al, 2000). In all, 98% of such mutations involve the large pocket domain of RB, which spans residues 393-928 (Harbour, 1998).…”

Section: Derepression Of Tfiiibmentioning

confidence: 99%

RNA polymerase III transcription and cancer

2004

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RNA polymerase (pol) III synthesizes a range of essential products, including tRNA, 5S rRNA and 7SL RNA, which are required for protein synthesis and trafficking. High rates of pol III transcription are necessary for cells to sustain growth. A wide range of transformed and tumour cell types have been shown to express elevated levels of pol III products. This review will summarize what is known about the mechanisms responsible for this deregulation. Some transforming agents have been shown to stimulate expression of the pol III-specific transcription factors TFIIIB or TFIIIC2. In addition, TFIIIB is bound and activated by several oncogenic proteins, including cMyc. Conversely, TFIIIB interacts in healthy cells with the tumour suppressors RB and p53. Indeed, the ability to limit pol III transcription through TFIIIB may contribute to their growth-suppression capacities. The function of p53 and/or RB is compromised in most if not all transformed cells; the resultant derepression of TFIIIB may provide an almost universal route to deregulate pol III transcription in cancers. In addition to effects on protein synthesis and growth, there is a precedent for a pol III product having oncogenic activity.

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Section: Derepression Of Tfiiibmentioning

confidence: 99%

RNA polymerase III transcription and cancer

2004

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“…Study of the rare pediatric eye cancer, retinoblastoma (MIM# 180200), has revealed fundamental mechanisms of cancer (DiCiommo et al, 2000). The initiating event in retinoblastoma development is the loss of function of both alleles of the prototypic tumor suppressor gene, RB1, which encodes a key cell-cycle negative regulatory transcription factor, pRB (Classon and Harlow, 2002).…”

Section: Introductionmentioning

confidence: 99%

KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers

et al. 2005

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Gain of chromosome 1q31-1q32 is seen in >50% of retinoblastoma and is common in other tumors. To define the minimal 1q region of gain, we determined genomic copy number by quantitative multiplex PCR of 14 sequence tagged sites (STSs) spanning 1q25.3-1q41. The most frequently gained STS at 1q32.1 (71%; 39 of 55 retinoblastoma) defined a 3.06 Mbp minimal region of gain between flanking markers, containing 14 genes. Of these, only KIF14, a putative chromokinesin, was overexpressed in various cancers by real-time RT-PCR. KIF14 mRNA was expressed in 20/22 retinoblastoma samples 100-1000-fold higher than in retina (t-test P ¼ 0.00002); cell lines (n ¼ 10) had higher levels than tumors (n ¼ 12) (P ¼ 0.009). KIF14 protein was overexpressed in retinoblastoma tumors and breast cancer cell lines by immunoblot. KIF14 was expressed in 4/4 breast cancer cell lines 31-92-fold higher than in normal breast tissue, in 5/5 medulloblastoma cell lines 22-79-fold higher than in fetal brain, and in 10/22 primary lung tumors 3-34-fold higher than in normal lung. Patients with lung tumors that overexpress KIF14 showed a trend toward decreased survival. KIF14 may thus be important in oncogenesis, and has promise as a prognostic indicator and therapeutic target.

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“…Moreover, pRb1/p105 is also involved in the apoptotic response by interacting with p53 pro-apoptotic pathway (Hsieh et al, 1997(Hsieh et al, , 1999Chan et al, 2001). Not withstanding the fact that mutation of Rb1/p105 is common to all retinoblastomas, much evidence indicates that loss of pRb1/p105 from a developing retinal cell is insufficient for malignancy (DiCiommo et al, 2000). The possibility that further mutations of other tumor suppressor genes could occur in sporadic retinoblastoma is supported by recent studies providing direct evidence that loss of pRb1/ p105 function leads to genome instability and predispose to cancer by increasing DNA mutation rate (Zheng and Lee, 2002).…”

Section: Introductionmentioning

confidence: 99%

Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach

et al. 2005

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Human retinoblastoma occurs in two forms (familial and sporadic) both due to biallelic mutation of the RB1/p105 gene even if its loss is insufficient for malignancy. We have recently reported that loss of expression of the retinoblastoma-related protein pRb2/p130 correlates with low apoptotic index, suggesting that RB2/p130 gene could be involved in retinoblastoma. Mutational analysis of RB2/ p130 in primary tumors showed a tight correlation between Exon 1 mutations and pRb2/p130 expression level in sporadic retinoblastoma. These mutations are located within a CpG-enriched region prone to de novo methylation. Analysis of RB2/p130 methylation status revealed that epigenetic events, most probably consequent to the Exon 1 mutations, determined the observed phenotype. Treatment of Weri-Rb1 cell line by 5-AzadC induced an increase in expression level of pRb2/p130, E2F1, p73 and p53. Overall, our results highlight a crucial role of epigenetic events in sporadic retinoblastoma, which opens a perspective for new therapeutic approaches.

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Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer

Cited by 115 publications

References 162 publications

RNA polymerase III transcription and cancer

RNA polymerase III transcription and cancer

KIF14 is a candidate oncogene in the 1q minimal region of genomic gain in multiple cancers

Genetic and epigenetic alterations of RB2/p130 tumor suppressor gene in human sporadic retinoblastoma: implications for pathogenesis and therapeutic approach

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