Functional roles of Akt signaling in mouse skin tumorigenesis.
The mouse skin carcinogenesis protocol is a unique model for understanding the molecular events leading to oncogenic transformation. Mutations in the Ha-ras gene, and the presence of functional cyclin D1 and the EGF receptor, have proven to be important in this system. However, the signal transduction pathways connecting these elements during mouse skin carcinogenesis are poorly understood. This paper studies the relevance of the Akt and ERK pathways in the different stages of chemically induced mouse skin tumors. Akt activity increases throughout the entire process, and its early activation is detected prior to increased cyclin D1 expression. ERK activity rises only during the later stages of malignant conversion. The observed early increase in Akt activity appears to be due to raised PI-3K activity. Other factors acting on Akt such as ILK activation and decreased PTEN phosphatase activity appear to be involved at the conversion stage. To further confirm the involvement of Akt in this process, PB keratinocytes were transfected with Akt and subsequently injected into nude mice. The expression of Akt accelerates tumorigenesis and contributes to increased malignancy of these keratinocytes as demonstrated by the rate of appearance, the growth and the histological characteristics of the tumors. Collectively, these data provide evidence that Akt activation is one of the key elements during the different steps of mouse skin tumorigenesis.
Segrelles
Carmen
C
Project on Cell and Molecular Biology and Gene Therapy, CIEMAT, Av. Complutense 22, E-28040 Madrid, Spain.
Ruiz
Sergio
S
Perez
Paloma
P
Murga
Cristina
C
Santos
Mirentxu
M
Budunova
Irina V
IV
Martínez
Jesús
J
Larcher
Fernando
F
Slaga
Thomas J
TJ
Gutkind
J Silvio
JS
Jorcano
Jose L
JL
Paramio
Jesús M
JM
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D002461:Cell Line, Transformed / Q000201:enzymology / Q000637:transplantation; D002467:Cell Nucleus / Q000201:enzymology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology / Q000637:transplantation; D020935:MAP Kinase Signaling System; D051379:Mice; D018632:Mice, Inbred SENCAR; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D051059:PTEN Phosphohydrolase; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D000099200:Scaffold Protein ILK
D015127:9,10-Dimethyl-1,2-benzanthracene; D002273:Carcinogens; D019938:Cyclin D1; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D000099200:Scaffold Protein ILK