This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, L. Articles by Lee, W.-H. Search for Related Content PubMed PubMed Citation Articles by Zheng, L. Articles by Lee, W.-H.

Deficiency of Retinoblastoma Gene in Mouse Embryonic Stem Cells Leads to Genetic Instability¹

Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245

Genetic instability has been recognized as a hallmark of human cancers. Retinoblastoma (Rb) tumor suppressor protein has an essential role in modulating cell cycle progression. However, there is no direct evidence supporting its role in maintaining genetic stability. Here, we developed a sensitive method to examine the level of chromosome instability by using retrovirus carrying both positive and negative selectable markers that integrated randomly into individual chromosomes, and the frequency of loss of this selectable chromosomal marker (LOM) in normal mammalian cells was measured. Our results showed that normal mouse embryonic stem (ES) cells had a very low frequency of LOMs, which was less than 10^-8/cell/generation. In Rb-/- mouse ES cells, the frequency was increased to approximately 10^-5/cell/generation, whereas in Rb+/- ES cells, the frequency was approximately 10^-7/cell/generation. LOMs was mediated mainly through chromosomal mechanisms and not through point mutations. These results, therefore, revealed that Rb, with a haploinsufficiency, plays a critical role in the maintenance of chromosome stability. The mystery of why Rb heterozygous carriers have early-onset tumor formation with high penetrance can be, at least, partially explained by this novel activity.

This article has been cited by other articles:

				S. V. Srinivasan, C. N. Mayhew, S. Schwemberger, W. Zagorski, and E. S. Knudsen RB Loss Promotes Aberrant Ploidy by Deregulating Levels and Activity of DNA Replication Factors J. Biol. Chem., August 17, 2007; 282(33): 23867 - 23877. [Abstract] [Full Text] [PDF]

				E. S. Knudsen and K. E. Knudsen Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Experimental Biology and Medicine, July 1, 2006; 231(7): 1271 - 1281. [Abstract] [Full Text] [PDF]

				X. Li, B. Guan, S. Maghami, and C. J. Bieberich NKX3.1 Is Regulated by Protein Kinase CK2 in Prostate Tumor Cells Mol. Cell. Biol., April 15, 2006; 26(8): 3008 - 3017. [Abstract] [Full Text] [PDF]

				S. R. Payne and C. J. Kemp Tumor suppressor genetics Carcinogenesis, December 1, 2005; 26(12): 2031 - 2045. [Abstract] [Full Text] [PDF]

				C. N. Mayhew, E. E. Bosco, S. R. Fox, T. Okaya, P. Tarapore, S. J. Schwemberger, G. F. Babcock, A. B. Lentsch, K. Fukasawa, and E. S. Knudsen Liver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy Cancer Res., June 1, 2005; 65(11): 4568 - 4577. [Abstract] [Full Text] [PDF]

				A. Lasorella, G. Rothschild, Y. Yokota, R. G. Russell, and A. Iavarone Id2 Mediates Tumor Initiation, Proliferation, and Angiogenesis in Rb Mutant Mice Mol. Cell. Biol., May 1, 2005; 25(9): 3563 - 3574. [Abstract] [Full Text] [PDF]

				Z. Zhou, A. Flesken-Nikitin, C. G. Levine, E. N. Shmidt, J. P. Eng, E. Yu. Nikitina, D. M. Spencer, and A. Yu. Nikitin Suppression of Melanotroph Carcinogenesis Leads to Accelerated Progression of Pituitary Anterior Lobe Tumors and Medullary Thyroid Carcinomas in Rb+/- Mice Cancer Res., February 1, 2005; 65(3): 787 - 796. [Abstract] [Full Text] [PDF]

				L. B. Smilenov, H. B. Lieberman, S. A. Mitchell, R. A. Baker, K. M. Hopkins, and E. J. Hall Combined Haploinsufficiency for ATM and RAD9 as a Factor in Cell Transformation, Apoptosis, and DNA Lesion Repair Dynamics Cancer Res., February 1, 2005; 65(3): 933 - 938. [Abstract] [Full Text] [PDF]

				N. Erdmann, Y. Liu, and L. Harrington Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice PNAS, April 20, 2004; 101(16): 6080 - 6085. [Abstract] [Full Text] [PDF]

				S. Duensing and K. Munger The Human Papillomavirus Type 16 E6 and E7 Oncoproteins Independently Induce Numerical and Structural Chromosome Instability Cancer Res., December 1, 2002; 62(23): 7075 - 7082. [Abstract] [Full Text] [PDF]

				C. R. Herzog, T. R. Devereux, B. Pittman, and M. You Carcinogenic Induction Directs the Selection of Allelic Losses in Mouse Lung Tumorigenesis Cancer Res., November 15, 2002; 62(22): 6424 - 6429. [Abstract] [Full Text] [PDF]

				A. Y. Nikitin, C.-Y. Liu, A. Flesken-Nikitin, C.-F. Chen, P.-L. Chen, and W.-H. Lee Cell Lineage-specific Effects Associated with Multiple Deficiencies of Tumor Susceptibility Genes in Msh2-/-Rb+/- Mice Cancer Res., September 15, 2002; 62(18): 5134 - 5138. [Abstract] [Full Text] [PDF]