Abstract
The p16/RB1 tumor suppressor pathway is inactivated in the vast majority, if not all, human cancers. The current paradigm is that p16 and RB1 function in a linear pathway to suppress tumorigenesis; however p16 is preferentially lost in human cancers suggesting that p16 has critical tumor suppressive functions not mediated through RB1. Carcinomas arise from transformed epithelial cells and account for 80% of adult malignancies highlighting the need to understand p16/RB1 pathway function in organ epithelia. Lung cancer is the leading cause of cancer deaths and is associated with p16/RB1 pathway deregulation. We demonstrate that p16 is upregulated in the lung epithelium after Rb1 ablation in genetically engineered mouse models. In contrast to fibroblasts, loss of RB1 family proteins, p107 or p130, did not result in p16 induction, demonstrating that p16 suppression is a unique RB1 pocket protein function in the lung epithelium in vivo. p16 upregulation did not induce cellular senescence but rather promoted survival of RB1-deficient lung epithelial progenitor cells. Mechanistic studies show that p16 protects RB1-deficient cells from DNA damage. Consequently, additional loss of p16 led to genetic instability and increased susceptibility to cellular immortalization and transformation. Mice with combined RB1/p16-deficient lungs developed lung tumors including aggressive metastatic lung cancers. These studies identify p16 loss as a molecular event that causes genetic instability and directly demonstrate that p16 protects against DNA damage in the absence of RB1 function providing an explanation for why p16 is preferentially targeted in human cancers.
Highlights
The tumor suppressor proteins p16 and RB1 function in a common pathway that is deregulated in the vast majority of human cancers.[1,2] The current paradigm is that p16 and RB1 function in a linear pathway wherein p16 blocks cell cycle progression by maintaining RB1 in a functionally active state by inhibiting Cyclin D/Cyclin-dependent kinase 4/6 dependent phosphorylation.[3]As p16 loss and Rb1 mutations both lead to loss of RB1 function, it is unclear why p16 and Rb1 are targeted in specific cancers and why p16 loss occurs much more frequently and in a wider variety of cancer types than does Rb1 mutation
Lung cancers are divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) with p16 loss being detected in up to 80% of NSCLC and biallelic Rb1 loss being obligatory for development of SCLC.[4,6,7,8]
P16 suppresses carcinogenesis independent of RB1 M Sen et al promoting tumor progression.[19]. These results suggest that p16 arrest with resistance to mitogenic and oncogenic stimuli.[18,23] associated cellular senescence antagonizes RB1-deficient carcino- Consistent with p16 induction not being associated with cellular genesis and provide evidence that p16 has tumor suppressive senescence, RB1-deficient lung epithelial cells proliferated in functions that are not mediated through RB1
Summary
The tumor suppressor proteins p16 and RB1 function in a common pathway that is deregulated in the vast majority of human cancers.[1,2] The current paradigm is that p16 and RB1 function in a linear pathway wherein p16 blocks cell cycle progression by maintaining RB1 in a functionally active state by inhibiting Cyclin D/Cyclin-dependent kinase 4/6 dependent phosphorylation.[3]. RB1 loss resulted in p16 induction after RB1 loss was not associated with cellular increased epithelial cell growth as compared to RB1 and senescence but rather protected lung epithelial progenitor cells p16-proficient control cells (Figure 1e). This is in direct contrast from DNA damage and development of aggressive lung cancers. Based on the well-established growth suppressive functions of p16, it was expected that p16 loss would enhance RB1-deficient
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
