c-fos is required for malignant progression of skin tumors.
The proto-oncogene c-fos is a major nuclear target for signal transduction pathways involved in the regulation of cell growth, differentiation, and transformation. Using the multistep skin carcinogenesis model, we have directly tested the ability of c-fos-deficient mice to develop cancer. Upon treatment with a tumor promoter, c-fos knockout mice carrying a v-H-ras transgene were able to develop benign tumors with similar kinetics and relative incidence as wild-type animals. However, c-fos-deficient papillomas quickly became very dry and hyperkeratinized, taking on an elongated, horny appearance. While wild-type papillomas eventually progressed into malignant tumors, c-fos-deficient tumors failed to undergo malignant conversion. Experiments in which v-H-ras-expressing keratinocytes were grafted onto nude mice suggest that c-fos-deficient cells have an intrinsic defect that hinders tumorigenesis. These results demonstrate that a member of the AP-1 family of transcription factors is required for the development of a malignant tumor.
Saez
E
E
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Rutberg
S E
SE
Mueller
E
E
Oppenheim
H
H
Smoluk
J
J
Yuspa
S H
SH
Spiegelman
B M
BM
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000078404:Epidermal Cells; D015870:Gene Expression / Q000502:physiology; D016762:Genes, fos / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics; D015603:Keratinocytes / Q000473:pathology; D007633:Keratins / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D009368:Neoplasm Transplantation; D015689:Oncogene Protein p21(ras) / Q000235:genetics*; D010212:Papilloma / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics
D018808:Transcription Factor AP-1; D007633:Keratins; D015689:Oncogene Protein p21(ras)