CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis

Abstract

Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth.

Cancer genetics: Finding the right mix

“…Although many studies have demonstrated the importance of orthotopic implantation in tumor formation, 5 this system provides a foundation with which to study melanoma mutations in the appropriate microenvironment. Similar studies in human keratinocytes 6 and prostate epithelial cells 7 reinforce the notion that reassembling the tumor environment permits the development of improved cancer models. Since recent work suggests that stromal cells contribute to tumor development, 8 such systems promise to allow one to dissect the interactions between tumor cells and stromal cells in transformation.…”

Suppression of fatty acid synthase in MCF-7 breast cancer cells by tea and tea polyphenols: a possible mechanism for their hypolipidemic effects

“…34 Several anabolic enzymes such as DNA polymerase, ribonucleotide reductase, FAS, etc are overexpressed in cell proliferation and tumor development. [35][36][37] Numerous studies have demonstrated the striking similarity between the tumor promotion process in Figure 6 A proposed mechanism for the suppression of EGCG and TF-3 on the expression of FAS through modulation of the EGF receptor/PI3K/Akt/Sp-1 signal transduction pathway. Abbreviations are: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; PI3K, phosphotidylinositol-3-kinase; PDK, phosphotidylinositol-3, 4, 5-triphosphate-dependent kinase; EGCG, epigallocatechin-3-gallate; TF-3, theaflavin-3,3 0 -digallate.…”

Ha-rasval12 induces HSP70b transcription via the HSE/HSF1 system, but HSP70b expression is suppressed in Ha-rasval12-transformed cells

“…The Ha-ras val12 oncogene, for example, induces growth arrest and senescence in primary cell cultures (Serrano et al, 1997), although in established cell lines it induces oncogenesis (Marshall, 1996;Lloyd, 1998;Hanahan and Weinberg, 2000). In primary cultures, Ras evokes growth arrest by activating proteins such as p53, p21, p16INK4A, CDK4 and p19ARF (Serrano et al, 1997;Ries et al, 2000;Lazarov et al, 2002). Development of an oncogenic phenotype in primary cultures may occur upon inactivation of one of them (Serrano et al, 1997;Sahai et al, 2001).…”