PMID- 24469052
OWN - NLM
STAT- MEDLINE
DCOM- 20150410
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 5
DP  - 2015 Jan 29
TI  - p53 suppresses carcinoma progression by inhibiting mTOR pathway activation.
PG  - 589-99
LID - 10.1038/onc.2013.589 [doi]
AB  - Genetic alterations in human cancers and murine models indicate that 
      retinoblastoma (Rb) and p53 have critical tumor suppressive functions in 
      retinoblastoma, a tumor of neural origin, and neuroendocrine tumors including 
      small cell lung cancer and medullary thyroid cancer (MTC). Rb inactivation is the 
      initiating lesion in retinoblastoma and current models propose that induction of 
      apoptosis is a key p53 tumor suppressive function. Genetic studies in mice, 
      however, indicate that other undefined p53 tumor suppressive functions are 
      operative in vivo. How p53 loss cooperates with Rb inactivation to promote 
      carcinogenesis is also not fully understood. In the current study, genetically 
      engineered mice were generated to determine the role of Rb and p53 in MTC 
      pathogenesis and test the hypothesis that p53 suppresses carcinogenesis by 
      inhibiting mammalian target of rapamycin (mTOR) signaling. Conditional Rb 
      ablation resulted in thyroid tumors mimicking human MTC, and additional p53 loss 
      led to rapid tumor progression. p53 suppressed tumorigenesis by inhibiting cell 
      cycle progression, but did not induce apoptosis. On the contrary, p53 loss led to 
      increased apoptosis that had to be overcome for tumor progression. The mTOR 
      activity was markedly increased in p53-deficient tumors and rapamycin treatment 
      suppressed tumor cell growth, identifying mTOR inhibition as a critical p53 tumor 
      suppressive function. Rapamycin treatment did not result in AKT/mitogen-activated 
      protein kinase activation, providing evidence that this feedback mechanism 
      operative in other cancers is not a general response to mTORC1 inhibition. 
      Together, these studies provide mechanistic links between genetic alterations and 
      aberrant signaling pathways critical in carcinogenesis, and identify essential Rb 
      and p53 tumor suppressive functions in vivo.
FAU - Akeno, N
AU  - Akeno N
AD  - Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH, USA.
FAU - Miller, A L
AU  - Miller AL
AD  - Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH, USA.
FAU - Ma, X
AU  - Ma X
AD  - Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH, USA.
FAU - Wikenheiser-Brokamp, K A
AU  - Wikenheiser-Brokamp KA
AD  - 1] Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical 
      Center, Cincinnati, OH, USA [2] Pulmonary Biology, Cincinnati Children's Hospital 
      Medical Center and Pathology and Laboratory Medicine, University of Cincinnati 
      College of Medicine, Cincinnati, OH, USA.
LA  - eng
GR  - R01 HL079193/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140127
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - Thyroid cancer, medullary
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Carcinoma, Neuroendocrine
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Transformation, Neoplastic/drug effects/*genetics
MH  - Humans
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Retinoblastoma Protein/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/administration & dosage
MH  - TOR Serine-Threonine Kinases/*genetics/metabolism
MH  - Thyroid Neoplasms/*genetics/pathology
MH  - Tumor Suppressor Protein p53/*genetics/metabolism
PMC - PMC4112184
MID - NIHMS551120
EDAT- 2014/01/29 06:00
MHDA- 2015/04/11 06:00
PMCR- 2015/07/29
CRDT- 2014/01/29 06:00
PHST- 2013/05/08 00:00 [received]
PHST- 2013/10/18 00:00 [revised]
PHST- 2013/12/18 00:00 [accepted]
PHST- 2014/01/29 06:00 [entrez]
PHST- 2014/01/29 06:00 [pubmed]
PHST- 2015/04/11 06:00 [medline]
PHST- 2015/07/29 00:00 [pmc-release]
AID - onc2013589 [pii]
AID - 10.1038/onc.2013.589 [doi]
PST - ppublish
SO  - Oncogene. 2015 Jan 29;34(5):589-99. doi: 10.1038/onc.2013.589. Epub 2014 Jan 27.