Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis

J. Dennemärker, T. Lohmüller, J. Mayerle, M. Tacke, M. M. Lerch, Lisa Coussens, C. Peters, T. Reinheckel

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

To define a functional role for the endosomal/lysosomal cysteine protease cathepsin L (Ctsl) during squamous carcinogenesis, we generated mice harboring a constitutive Ctsl deficiency in addition to epithelial expression of the human papillomavirus type 16 oncogenes (human cytokeratin 14 (K14)-HPV16). We found enhanced tumor progression and metastasis in the absence of Ctsl. As tumor progression in K14-HPV16 mice is dependent on inflammation and angiogenesis, we examined immune cell infiltration and vascularization without finding any effect of the Ctsl genotype. In contrast, keratinocyte-specific transgenic expression of cathepsin V, the human orthologue of mouse Ctsl, in otherwise Ctsl-deficient K14-HPV16 mice restored the phenotype observed in the control HPV16 skin. To better understand this phenotype at the molecular level, we measured several oncogenic signal transduction pathways in primary keratinocytes on stimulation with keratinocyte-conditioned cell culture medium. We found increased activation of protein kinase B/Akt and mitogen-activated protein kinase pathways in protease-deficient cells, especially if treated with media conditioned by Ctsl-deficient keratinocytes. Similarly, the level of active GTP-Ras was increased in Ctsl-deficient epidermis. We conclude that Ctsl is critical for the termination of growth factor signaling in the endosomal/lysosomal compartment of keratinocytes and, therefore, functions as an anti-tumor protease.

Original languageEnglish (US)
Pages (from-to)1611-1621
Number of pages11
JournalOncogene
Volume29
Issue number11
DOIs
StatePublished - Mar 2010
Externally publishedYes

Fingerprint

Cathepsin L
Cysteine Proteases
Epidermis
Keratinocytes
Neoplasms
Conditioned Culture Medium
Peptide Hydrolases
Keratin-14
Phenotype
Proto-Oncogene Proteins c-akt
Human papillomavirus 16
Guanosine Triphosphate
Mitogen-Activated Protein Kinases
Oncogenes
Signal Transduction
Intercellular Signaling Peptides and Proteins
Carcinogenesis
Cell Culture Techniques
Genotype
Neoplasm Metastasis

Keywords

  • Cathepsin
  • Mouse model
  • Protease
  • Skin cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Dennemärker, J., Lohmüller, T., Mayerle, J., Tacke, M., Lerch, M. M., Coussens, L., ... Reinheckel, T. (2010). Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis. Oncogene, 29(11), 1611-1621. https://doi.org/10.1038/onc.2009.466

Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis. / Dennemärker, J.; Lohmüller, T.; Mayerle, J.; Tacke, M.; Lerch, M. M.; Coussens, Lisa; Peters, C.; Reinheckel, T.

In: Oncogene, Vol. 29, No. 11, 03.2010, p. 1611-1621.

Research output: Contribution to journalArticle

Dennemärker, J, Lohmüller, T, Mayerle, J, Tacke, M, Lerch, MM, Coussens, L, Peters, C & Reinheckel, T 2010, 'Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis', Oncogene, vol. 29, no. 11, pp. 1611-1621. https://doi.org/10.1038/onc.2009.466
Dennemärker, J. ; Lohmüller, T. ; Mayerle, J. ; Tacke, M. ; Lerch, M. M. ; Coussens, Lisa ; Peters, C. ; Reinheckel, T. / Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis. In: Oncogene. 2010 ; Vol. 29, No. 11. pp. 1611-1621.
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