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mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK.

Publication ,  Journal Article
Wu, H; He, D; Biswas, S; Shafiquzzaman, M; Zhou, X; Charron, J; Wang, Y; Nayak, BK; Habib, SL; Liu, H; Li, B
Published in: Cancer Res
June 15, 2021

Renal cell carcinoma (RCC) mainly originates from renal proximal tubules. Intriguingly, disruption of genes frequently mutated in human RCC samples thus far has only generated RCC originated from other renal tubule parts in mouse models. This hampers our understanding of the pathogenesis of RCC. Here we show that mTOR signaling, often activated in RCC samples, initiates RCC development from renal proximal tubules. Ablation of Tsc1, encoding an mTOR suppressor, in proximal tubule cells led to multiple precancerous renal cysts. mTOR activation increased MEK1 expression and ERK activation, and Mek1 ablation or inhibition diminished cyst formation in Tsc1-deficient mice. mTOR activation also increased MKK6 expression and p38MAPK activation, and ablation of the p38α-encoding gene further enhanced cyst formation and led to RCC with clear cell RCC features. Mechanistically, Tsc1 deletion induced p53 and p16 expression in a p38MAPK-dependent manner, and deleting Tsc1 and Trp53 or Cdkn2a (encoding p16) enhanced renal cell carcinogenesis. Thus, mTOR activation in combination with inactivation of the p38MAPK-p53/p16 pathway drives RCC development from renal proximal tubules. Moreover, this study uncovers previously unidentified mechanisms by which mTOR controls cell proliferation and suggests the MEK-ERK axis to be a potential target for treatment of RCC. SIGNIFICANCE: Mouse modeling studies show that mTOR activation in combination with inactivation of the p38MAPK-p53/p16 axis initiates renal cell carcinoma that mimics human disease, identifying potential therapeutic targets for RCC treatment.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

June 15, 2021

Volume

81

Issue

12

Start / End Page

3174 / 3186

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinase 14
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
 

Citation

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Chicago
ICMJE
MLA
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Wu, H., He, D., Biswas, S., Shafiquzzaman, M., Zhou, X., Charron, J., … Li, B. (2021). mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK. Cancer Res, 81(12), 3174–3186. https://doi.org/10.1158/0008-5472.CAN-20-3979
Wu, Hongguang, Dan He, Soma Biswas, Md Shafiquzzaman, Xin Zhou, Jean Charron, Yibin Wang, et al. “mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK.Cancer Res 81, no. 12 (June 15, 2021): 3174–86. https://doi.org/10.1158/0008-5472.CAN-20-3979.
Wu H, He D, Biswas S, Shafiquzzaman M, Zhou X, Charron J, et al. mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK. Cancer Res. 2021 Jun 15;81(12):3174–86.
Wu, Hongguang, et al. “mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK.Cancer Res, vol. 81, no. 12, June 2021, pp. 3174–86. Pubmed, doi:10.1158/0008-5472.CAN-20-3979.
Wu H, He D, Biswas S, Shafiquzzaman M, Zhou X, Charron J, Wang Y, Nayak BK, Habib SL, Liu H, Li B. mTOR Activation Initiates Renal Cell Carcinoma Development by Coordinating ERK and p38MAPK. Cancer Res. 2021 Jun 15;81(12):3174–3186.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

June 15, 2021

Volume

81

Issue

12

Start / End Page

3174 / 3186

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinase 14
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice