Retinoblastoma Family Proteins Have Distinct Functions in Pulmonary Epithelial Cells In vivo Critical for Suppressing Cell Growth and Tumorigenesis
Open Access
- 11 November 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (22), 8733-8741
- https://doi.org/10.1158/0008-5472.can-09-1359
Abstract
Lung cancer is the leading cause of cancer deaths, accounting for more deaths than breast, colon, and prostate cancer combined. The retinoblastoma (Rb)/p16 tumor suppressive pathway is deregulated in most cancers. Loss of p16 occurs more frequently than Rb loss, suggesting that p16 suppresses cancer by regulating Rb as well as the related proteins p107 and p130. However, direct evidence demonstrating that p130 or p107 cooperate with Rb to suppress epithelial cancers associated with p16 loss is currently lacking. Moreover, the roles of p130 and p107 in lung cancer are not clear. In the present studies, Rb ablation was targeted to the lung epithelium in wild-type, p107, or p130 null mice to determine unique and overlapping Rb family functions critical in tumor suppression. Rb ablation during development resulted in marked epithelial abnormalities despite p107 upregulation. In contrast, p130 and p107 were not required during development but had distinct functions in the Rb-deficient epithelium: p107 was required to suppress proliferation, whereas a novel proapoptotic function was identified for p130. Adult Rb-ablated lungs lacked the epithelial phenotype seen at birth and showed compensatory p107 upregulation and p16 induction in epithelial cell lineages that share phenotypic characteristics with human non–small cell lung cancers (NSCLC) that frequently show p16 loss. Importantly, Rb/p107-deficient, but not Rb/p130-deficient, lungs developed tumors resembling NSCLC. Taken together, these studies identify distinct Rb family functions critical in controlling epithelial cell growth, and provide direct evidence that p107 cooperates with Rb to protect against a common adult cancer. [Cancer Res 2009;69(22):8733–41]Keywords
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This publication has 38 references indexed in Scilit:
- Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of RbMolecular and Cellular Biology, 2005
- Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130Genes & Development, 2004
- Generalized lacZ expression with the ROSA26 Cre reporter strainNature Genetics, 1999
- p107 is a suppressor of retinoblastoma development in pRb-deficient miceGenes & Development, 1998
- Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinomaProceedings of the National Academy of Sciences of the United States of America, 1997
- Shared role of the pRB-related p130 and p107 proteins in limb development.Genes & Development, 1996
- Targeted disruption of p107: functional overlap between p107 and Rb.Genes & Development, 1996
- Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.Proceedings of the National Academy of Sciences of the United States of America, 1995
- Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB.1994
- Requirement for a functional Rb-1 gene in murine developmentNature, 1992