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

G. A. Niehans, Robert A Kratzke, M. K. Froberg, D. M. Aeppli, P. L. Nguyen, J. Geradts

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56 Scopus citations


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 in 15/79 cases (19%). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16(INK4a), or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16(INK4a) and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16(INK4a) and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16(INK4a) can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.

Original languageEnglish (US)
Pages (from-to)1175-1184
Number of pages10
JournalBritish Journal of Cancer
Issue number8
StatePublished - 1999

Bibliographical note

Funding Information:
We appreciate the technical assistance of Ms Pat Rene and the staff of the Minneapolis Department of Veterans Affairs Medical Center Histology Laboratory: Sue Dachel, Josie Robida, Pamela Karbon, Dennis Knapp and Wendy Larson. We also appreciate the immunohistochemical expertise of Clint E Lincoln, who performed the Rb protein immunostains, and of Michael Sakata and Robert Maynard, who performed the p16INK4a immunostains. Supported by a Merit Grant from the Department of Veterans Affairs Medical Research Service (RK), and a grant from the University of North Carolina Research Council (JG).


  • Bladder neoplasms
  • Cyclin D1
  • Retinoblastoma protein
  • p16(1NK4)
  • p53


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