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Earlier Onset of Melanotroph Carcinogenesis in Mice with Inherited Mutant Paternal Allele of the Retinoblastoma Gene¹

Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, Texas 78245-3207

The role of genomic imprinting in the development of tumors with defective retinoblastoma protein function remains debatable. Disruption of either parental allele of the murine retinoblastoma (Rb) gene is sufficient for spontaneous melanotroph carcinogenesis to occur in almost all Rb^+/- mice. Nevertheless, mice with a disrupted paternal Rb allele succumb to tumors faster. In these animals, the first foci of proliferating atypical Rb-negative cells appear and progress to overtly malignant tumors earlier. In addition, more foci of early atypical proliferation are observed. In Rb^+/- mice, however, parental origin influences neither Rb expression nor proliferation of melanotrophs. Accordingly, Rb^-/- mice rescued by the human RB transgene transmitted either paternally or maternally have similar survival rates. Taken together, the data point to the existence of an imprinted gene in an Rb-linked locus. The function of this gene affects the onset of melanotroph carcinogenesis, likely by controlling preferential survival of the cells with secondary loss of the Rb maternal allele. Rb^+/- mice may serve as useful models to identify and characterize genomic imprinting mechanisms influencing carcinogenesis associated with Rb loss of function.

¹ Supported by NIH Grants EY05785 and CA58318 (to W-H. L.), a grant from the Tobacco Council for Research, and a Physician's Research Training Award (to D. J. R.) from the American Cancer Society.

² Present address: Division of Nephrology, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284.

³ To whom requests for reprints should be addressed, at Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center, 15355 Lambda Drive, San Antonio, TX 78245-3207. Phone: (210) 567-7351; Fax: (210) 567-7377; E-mail: leew@uthscsa.edu.

Received 7/24/97. Accepted 8/13/97.

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