p53 and Rb Immunostaining in
Locally Advanced Bladder Cancer:
Relation to Prognostic Variables
and Predictive Value for the Local
Response to Radical Radiotherapy

Jahnson, Staffan; Risberg, B; Karlsson, Mats G.; Westman, Gunnar; Bergstrom, R; Pedersen, J.

doi:10.1159/000475038

Cited by 46 publications

(24 citation statements)

References 8 publications

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“…We identified loss of Rb protein in 29% of invasive transitional cell carcinomas of the bladder treated by cystectomy (23/79 cases). This correlates well with the frequency of Rb protein loss reported in other series, which has ranged from 16% to 46% (Cordon-Cardo et al, 1992;Logothetis et al, 1992;Jahnson et al, 1995;Lipponen and Liukkonen, 1995;Têtu et al, 1996;Cote et al, 1998). We also identified loss of the p16 INK4a tumour suppressor gene product in 15/79 carcinomas (19%).…”

Section: supporting

confidence: 91%

“…We did not find any link between p16 INK4a status and outcome. Based upon previous studies (Lipponen, 1993;Sarkis et al, 1993;Esrig et al, 1994;Cote et al, 1998), we anticipated poorer survival among patients with p53-abnormal tumours, although other groups have published conflicting results (Jahnson et al, 1995;Vet et al, 1995;Glick et al, 1996). We did not find an association between abnormal p53 protein accumulation and poor outcome among our cohort of patients with invasive transitional cell carcinomas treated by cystectomy.…”

Section: supporting

confidence: 48%

“…The relationship between p16 INK4a protein expression and outcome in bladder carcinoma has not been previously studied, although one report suggested that bladder carcinomas with deletion of the p16 INK4a gene are generally of low stage and grade . A number of previous papers have reported shorter survival times among patients with Rb-deleted bladder carcinomas (CordonCardo et al, 1992;Logothetis et al, 1992;Lipponen and Liukkonen, 1995;Cote et al, 1998), although others have not found such an association (Jahnson et al, 1995;Têtu et al, 1996). In our series, there was a trend toward poorer outcome for Rbdeleted tumours (Figure 4;  = 0.2), which might well have reached significance with a larger cohort.…”

Section: contrasting

confidence: 42%

“…While loss of Rb protein (Cordon-Cardo et al, 1992;Logothetis et al, 1992;Jahnson et al, 1995;Lipponen and Liukkonen, 1995;Têtu et al, 1996;Cote et al, 1998), deletions of the p16 INK4a gene Packenham et al, 1995;Williamson et al, 1995), and cyclin D1 overexpression (Bringuier et al, 1996;Lee et al, 1997;Shin et al, 1997) have previously been reported in transitional cell carcinomas, this is the first large study to examine loss of p16 INK4a at the more sensitive protein level, and to document the interrelationship of changes in each of these three components of the G1 checkpoint in the same set of bladder cancers.…”

Section: mentioning

confidence: 79%

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G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

et al. 1999

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To acquire a neoplastic phenotype, cells must disable multiple regulatory mechanisms including cell cycle control . Abrogation of the G1 cell cycle checkpoint occurs in many malignancies. Key components of the checkpoint include retinoblastoma protein (Rb), cyclin D1 (also known as bcl-1 and PRAD-1), and the cyclin-dependent kinase inhibitor p16 INK4a . In normal cells, the Rb protein acts as a cell cycle brake while in its active, hypophosphorylated state. Cyclin D1 is a short-lived protein with a half-life of 30 min or less. When cyclin D1 is induced in early G1 by mitogenic signals such as growth factors, it binds to and activates the cyclin-dependent kinases CDK4 and CDK6, and these cyclin-kinase complexes then phosphorylate and inactivate the Rb protein, allowing the cell to proceed into S phase (reviewed by Strauss et al, 1995). p16 INK4a binds to CDK-cyclin complexes and blocks phosphorylation of the Rb protein. Since inactivation of Rb enhances transcription of p16 INK4a , p16 INK4a may act in normal cells as part of a negative feedback loop to turn off CDK4-cyclin D activity once the cell has passed the G1 restriction point (Serrano et al, 1993;Li et al, 1994;Parry et al, 1995). Thus, inactivation of either p16 INK4a or Rb protein shifts the balance toward continued cell proliferation, as does amplification/overexpression of cyclin D1.Abnormalities of individual components of the Rb/cyclin D1/p16 INK4a pathway have been previously reported in cases of transitional cell carcinoma of the bladder (Cordon-Cardo et al, 1992;Logothetis et al, 1992;Geradts et al, 1995;Gruis et al, 1995;Orlow et al, 1995;Packenham et al, 1995;Williamson et al, 1995;Bringuier et al, 1996;Lee et al, 1997;Shin et al, 1997). In order to assess the overall frequency of G1 checkpoint defects in bladder carcinoma, and to examine the interrelationship between abnormalities in component proteins, we studied a series of 79 transitional cell carcinomas for evidence of cyclin D1 overexpression or loss of Rb or p16 INK4a proteins, using immunohistochemistry. The p53 status of these tumours was also assessed via immunohistochemistry, since p53 influences cell cycle control through an independent pathway mediated by p21 WAF1/CIP1 (El-Deiry et al, 1993).  Case selection and patient informationMost cases (77 of 79) were drawn from a previously published series (Nguyen et al, 1994) Summary The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16 INK4a , are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16 INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16 INK4a , which occurred i...

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Section: supporting

confidence: 91%

Section: supporting

confidence: 48%

Section: contrasting

confidence: 42%

Section: mentioning

confidence: 79%

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G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

et al. 1999

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show abstract

“…The relationship between p16 INK4a protein expression and outcome in bladder carcinoma has not been previously studied, although one report suggested that bladder carcinomas with deletion of the p16 INK4a gene are generally of low stage and grade . A number of previous papers have reported shorter survival times among patients with Rb-deleted bladder carcinomas (CordonCardo et al, 1992;Logothetis et al, 1992;Lipponen and Liukkonen, 1995;Cote et al, 1998), although others have not found such an association (Jahnson et al, 1995;Têtu et al, 1996). In our series, there was a trend toward poorer outcome for Rbdeleted tumours (Figure 4; P = 0.2), which might well have reached significance with a larger cohort.…”

Section: Discussioncontrasting

confidence: 43%

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

et al. 1999

View full text Add to dashboard Cite

To acquire a neoplastic phenotype, cells must disable multiple regulatory mechanisms including cell cycle control . Abrogation of the G1 cell cycle checkpoint occurs in many malignancies. Key components of the checkpoint include retinoblastoma protein (Rb), cyclin D1 (also known as bcl-1 and PRAD-1), and the cyclin-dependent kinase inhibitor p16 INK4a . In normal cells, the Rb protein acts as a cell cycle brake while in its active, hypophosphorylated state. Cyclin D1 is a short-lived protein with a half-life of 30 min or less. When cyclin D1 is induced in early G1 by mitogenic signals such as growth factors, it binds to and activates the cyclin-dependent kinases CDK4 and CDK6, and these cyclin-kinase complexes then phosphorylate and inactivate the Rb protein, allowing the cell to proceed into S phase (reviewed by Strauss et al, 1995). p16 INK4a binds to CDK-cyclin complexes and blocks phosphorylation of the Rb protein. Since inactivation of Rb enhances transcription of p16 INK4a , p16 INK4a may act in normal cells as part of a negative feedback loop to turn off CDK4-cyclin D activity once the cell has passed the G1 restriction point (Serrano et al, 1993;Li et al, 1994;Parry et al, 1995). Thus, inactivation of either p16 INK4a or Rb protein shifts the balance toward continued cell proliferation, as does amplification/overexpression of cyclin D1.Abnormalities of individual components of the Rb/cyclin D1/p16 INK4a pathway have been previously reported in cases of transitional cell carcinoma of the bladder (Cordon-Cardo et al, 1992;Logothetis et al, 1992;Geradts et al, 1995;Gruis et al, 1995;Orlow et al, 1995;Packenham et al, 1995;Williamson et al, 1995;Bringuier et al, 1996;Lee et al, 1997;Shin et al, 1997). In order to assess the overall frequency of G1 checkpoint defects in bladder carcinoma, and to examine the interrelationship between abnormalities in component proteins, we studied a series of 79 transitional cell carcinomas for evidence of cyclin D1 overexpression or loss of Rb or p16 INK4a proteins, using immunohistochemistry. The p53 status of these tumours was also assessed via immunohistochemistry, since p53 influences cell cycle control through an independent pathway mediated by p21 WAF1/CIP1 (El-Deiry et al, 1993). MATERIALS AND METHODS Case selection and patient informationMost cases (77 of 79) were drawn from a previously published series (Nguyen et al, 1994) Summary The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16 INK4a , are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16 INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16 INK4a , which occurred i...

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Tumor mapping of regional immunostaining for p21, p53, and mdm2 in locally advanced bladder carcinoma

Jahnson¹,

Karlsson²

2000

Cancer

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p53 and Rb Immunostaining in Locally Advanced Bladder Cancer: Relation to Prognostic Variables and Predictive Value for the Local Response to Radical Radiotherapy

Cited by 46 publications

References 8 publications

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

Tumor mapping of regional immunostaining for p21, p53, and mdm2 in locally advanced bladder carcinoma

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