Expression of p16 induces transcriptional downregulation of the RB gene

Fang, Xianjun; Jin, Xiaomei; Xu, Hong Ji; Liu, Lin; Peng, Hong; Hogg, David; Roth, Jack A.; Yang, Yu Shih; Xu, Fengji; Bast, Robert C.; Mills, Gordon B.

doi:10.1038/sj.onc.1201525

Cited by 67 publications

(59 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The p16-sensitive SK-OV-3 and MCF-7 (control) cell lines underwent a shift in the expression of Rb protein to the fully active hypophosphorylated state following infection with Ad-p16, consistent with their cessation of growth. Notably, we observed a decrease in the total level of Rb protein, consistent with the ®ndings of Fang et al (1998) who previously demonstrated that overexpression of p16 appears to down-regulate Rb expression. In addition, both cell lines underwent a signi®cant decrease both in the expression of cyclin A, which is ordinarily expressed upon entry into S phase and maintained throughout G2/M, and the mitotic phase cyclin B1 (Figure 4).…”

Section: Coexpression Of Rb P16 and Cyclin D1 In Ovarian Cancerssupporting

confidence: 92%

“…Although less pronounced than that observed in the p16-sensitive SK-OV-3 and MCF-7 cell lines, all three of the p16-insensitive ovarian cancer cell lines (in addition to the HBL-100 control cell line) showed a discernable decrease in the total level of Rb protein expressed following ectopic p16 overexpression. This observation, again supports the role of p16 as a negative regulator of Rb expression as proposed by Fang et al (1998).…”

Section: Coexpression Of Rb P16 and Cyclin D1 In Ovarian Cancerssupporting

confidence: 88%

“…However, no data demonstrating endogenous p16 expression by this cell line was presented (Wolf et al, 1999). Furthermore, Fang et al (1998) have presented clear evidence that OVCA 420 cells do not express p16. Therefore, the signi®cance of the experiments carried out in OVCA 420 cells for evaluating the relationship between endogenous p16 status and sensitivity to p16 overexpression is di cult to interpret unambiguously.…”

Section: Discussionmentioning

confidence: 91%

See 2 more Smart Citations

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

2000

View full text Add to dashboard Cite

Defects of the`Rb/cyclin D1/p16 pathway' have been shown to play a critical role in the development of virtually all human malignancies assessed. To determine the contribution of G1 phase cell cycle defects to ovarian tumorigenesis, we have examined a panel of normal and tumor ovarian tissues and ovarian cancer cell lines for the expression of Rb, p16 and cyclin D1 proteins. Unlike most types of human cancer whose development involves the loss of either Rb or p16 expression, we observed the coexpression of Rb, p16 and cyclin D1 in 82% of ovarian cancer tissues and cell lines. Furthermore, the growth and cell cycle distribution pro®les of three ovarian cancer cell lines (ES-2, PA-1 and NIH OVCAR-3) that coexpressed Rb and p16, were found to be una ected by adenoviral-mediated overexpression of functional p16 protein, indicating the existence of a defect(s) downstream from p16 in these cells. By contrast overexpression of ectopic p16 in the one ovarian cancer cell line (SK-OV-3) that expressed Rb but lacked p16 protein, resulted in a G1 growth arrest. These data suggest that defects of the`Rb/cyclin D1/p16 pathway', other than the loss of Rb or p16, may play a major role in the development of ovarian cancer. Oncogene (2000) 19, 258 ± 264.

show abstract

Section: Coexpression Of Rb P16 and Cyclin D1 In Ovarian Cancerssupporting

confidence: 92%

Section: Coexpression Of Rb P16 and Cyclin D1 In Ovarian Cancerssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

2000

View full text Add to dashboard Cite

show abstract

“…Although direct evidence to support this concept has recently been reported (Fang et al, 1998), other possibilities exist as the basis for the RB overexpression observed secondary to functional p16 loss which could be, in fact, more likely. This conclusion is drawn from the well documented recent report that cyclin D: Cdk4/6 complexes hypo-phosphorylate RB to their active forms rather than hyper-phosphorylate RB to their inactive forms (Ezhevski et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

“…Direct evidence to support a role for p16 as a modulator of overall RB expression levels recently has been reported (Fang et al, 1998). Wild-type p16 was transferred into ovarian cancer cell lines as well as a bladder cancer cell line, all of which were p16-negative and RB-positive.…”

Section: Introductionmentioning

confidence: 97%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

View full text Add to dashboard Cite

Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, con®rming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

show abstract

Alteration of pRb/p16/cdk4 regulation in human osteosarcoma

et al. 1999

View full text Add to dashboard Cite

Cell‐cycle regulation depends on a fine balance between cyclin‐cyclin‐dependent kinase complexes and a family of kinase inhibitors that bind cyclin‐cdk complexes and block their activity. To investigate the role of mechanisms regulating cell‐cycle progression in human osteosarcomas (OS), pRb/p16/cdk4 expression was analyzed in 39 high‐grade OS; 19 of these developed metastasis during follow‐up. Positive reaction for functional pRB was shown by 18/39 (46%) OS, while 21/39 (54%) were negative. A higher probability of metastasis was seen in patients with negative pRb expression (p < 0.05). Furthermore, while functional pRb and D1 expression are inversely associated to metastasis occurrence, the presence of D1/cdk4 complex in our study was related to poor prognosis. We found that 10/18 pRb‐positive and 14/21 pRb‐negative tumors were p16‐positive. No significant correlation was found between pRb and p16 expression. On the other hand, high cdk4 levels in p16‐positive tumors as compared with p16‐negative tumors resulted in a positive association between p16 and cdk4 expression (Chi squared = 5.98; p = 0.01). No extensive p16INK4A genomic alterations were found in tumors lacking p16‐protein expression. To determine which mechanisms are involved in the down‐regulation of p16 protein, the methylation status of the p16INK4 gene was evaluated on the 15 p16‐negative tumors: 8 samples showed 5′ CpG‐island methylation; 4/8 had a complete methylation status, while in the remaining 4 the gene was only partially methylated. These data confirm the role of the pRb/p16/cdk4 pathway in OS development. Int. J. Cancer (Pred. Oncol.) 84:489–493, 1999. © 1999 Wiley‐Liss, Inc.

show abstract

Expression of p16 induces transcriptional downregulation of the RB gene

Cited by 67 publications

References 24 publications

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Alteration of pRb/p16/cdk4 regulation in human osteosarcoma

Contact Info

Product

Resources

About