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2017 ; 6
(4
): e320
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p16 controls epithelial cell growth and suppresses carcinogenesis through
mechanisms that do not require RB1 function
#MMPMID28414317
Sen M
; Akeno N
; Reece A
; Miller AL
; Simpson DS
; Wikenheiser-Brokamp KA
Oncogenesis
2017[Apr]; 6
(4
): e320
PMID28414317
show ga
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.