PTEN loss promotes ras^Ha-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via rasHa-independent pathways.

Yao, D., Alexander, C.L., Quinn, J.A., Porter, M.J., Wu, H. and Greenhalgh, D.A. (2006) PTEN loss promotes ras^Ha-mediated papillomatogenesis via dual up-regulation of AKT activity and cell cycle deregulation but malignant conversion proceeds via rasHa-independent pathways. Cancer Research, 66(3), pp. 1302-1312.

Abstract

PTEN tumor suppressor gene failure in ras<SUP>Ha</SUP>-activated skin carcinogenesis was investigated by mating exon 5 floxed-PTEN [5PTEN] mice to HK1.ras mice that expressed a RU486-inducible cre recombinase [K14.creP]. PTEN inactivation in K14.cre/Pten<SUP>flx/flx</SUP> keratinocytes resulted in epidermal hyperplasia/hyperkeratosis and novel TPA-promoted papillomas, whilst HK1.ras/K14.cre/Pten<SUP>flx/fl</SUP>x cohorts displayed a rapid onset of papillomatogenesis due to a synergism of increased AKT activity and ERK elevation. High BrdU labeling in D5PTEN papillomas demonstrated that a second promotion mechanism centered on failures in cell cycle control. Elevated cyclin D1 was associated with both HK1.ras/ERK and D5PTEN-mediated AKT signaling, while cyclin E2 overexpression appeared dependent on PTEN loss. Spontaneous HK1.ras/DPTEN malignant conversion was rare, whereas TPA promotion resulted in conversion with high frequency. On comparison to all previous HK1.ras carcinomas, such TPA-induced carcinomas expressed atypical retention of keratin K1 and lack of K13, a unique marker profile exhibited by TPA-induced K14.cre/Pten<SUP>flx/flx</SUP> papillomas that also lacked endogenous c-rasHa activation. Moreover, in all PTEN-null tumors levels of rasHa-associated total-ERK protein became reduced, whilst phospho-ERK and cyclin D1 were lowered in late-stage papillomas returning to elevated levels, alongside increased cyclin E2 expression, in TPA-derived carcinomas. Thus, during early papillomatogenesis, PTEN loss promotes rasHa initiation via elevation of AKT activity and synergistic failures in cyclin regulation. However, in progression, reduced ras-associated ERK protein and activity, increased D5PTEN-associated cyclin E2 expression and unique K1/K13 profiles following TPA treatment, suggests that PTEN loss, rather than rasHa activation, gives rise to a population of cells with greater malignant potential.

• Item Type: Articles
• Keywords: inducible gene switch, transgenic skin carcinogenesis,tumour progression keratinocyte differentiation, ras fos PTEN AKT GSK3b ERK, cyclins D, E2
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Greenhalgh, Dr David and Yao, Dr Denggao
• Authors: Yao, D., Alexander, C.L., Quinn, J.A., Porter, M.J., Wu, H., and Greenhalgh, D.A.
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Clinical Specialities
• Research Group: Section of Dermatology
• Journal Name: Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 0008-5472
• Copyright Holders: Copyright © 2006 American Association for Cancer Research
• First Published: First published in Cancer Research 66(3):1302-1312
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher