Lack of Cyclin-Dependent Kinase 4 Inhibits c-myc Tumorigenic Activities in Epithelial Tissues

Abstract

The proto-oncogene c-myc encodes a transcription factor that is implicated in the regulation of cellular proliferation, differentiation, and apoptosis and that has also been found to be deregulated in several forms of human and experimental tumors. We have shown that forced expression of c-myc in epithelial tissues of transgenic mice (K5-Myc) resulted in keratinocyte hyperproliferation and the development of spontaneous tumors in the skin and oral cavity. Although a number of genes involved in cancer development are regulated by c-myc, the actual mechanisms leading to Myc-induced neoplasia are not known. Among the genes regulated by Myc is the cyclin-dependent kinase 4 (CDK4) gene. Interestingly, previous studies from our laboratory showed that the overexpression of CDK4 led to keratinocyte hyperproliferation, although no spontaneous tumor development was observed. Thus, we tested the hypothesis that CDK4 may be one of the critical downstream genes involved in Myc carcinogenesis. Our results showed that CDK4 inhibition in K5-Myc transgenic mice resulted in the complete inhibition of tumor development, suggesting that CDK4 is a critical mediator of tumor formation induced by deregulated Myc. Furthermore, a lack of CDK4 expression resulted in marked decreases in epidermal thickness and keratinocyte proliferation compared to the results obtained for K5-Myc littermates. Biochemical analysis of the K5-Myc epidermis showed that CDK4 mediates the proliferative activities of Myc by sequestering p21Cip1 and p27 Kip1 and thereby indirectly activating CDK2 kinase activity. These results show that CDK4 mediates the proliferative and oncogenic activities of Myc in vivo through a mechanism that involves the sequestration of specific CDK inhibitors.

Cyclin a but not cyclin D1 is essential for c‐myc‐modulated cell‐cycle progression

“…Cdk4 provides a direct link between c-myc and cell-cycle regulation (Hermeking et al, 2000) and lack of Cdk4 inhibits c-myc's tumorgenic activities in epithelial tissues (Ortega et al, 2002). p21 and p27 inhibit Cdk2 kinase activity regardless of whether Cdk2 binds cyclin E or cyclin A. p21 and p27 are also capable of binding to cyclin D-Cdk4/6 complexes (Miliani de Marval et al, 2004).…”

Living with or without cyclins and cyclin-dependent kinases

“…Indeed, we already know that animals lacking Cdk4 are completely refractory to Ras-mediated skin carcinogenesis in vivo, whereas Cdk4 deficiency has no effect on the normal proliferation of keratinocytes in vitro (Rodriguez-Puebla et al 2002). Inactivation of Cdk4 also completely protects transgenic mice expressing cMyc under the control of the keratin-5 promoter from developing epithelial tumors (Miliani de Marval et al 2004). Similarly, cyclin D1 inactivation confers resistance to breast cancers induced by oncogenic Neu or Ras transgenes targeted to the mammary gland and to intestinal tumors resulting from Apc loss and constitutive ␤-catenin signaling (Hulit et al 2004).…”

Killing cells by targeting mitosis

“…4 The analysis of gene-targeted mouse models indicated that Cdk2, Cdk4 and Cdk6 are only essential for the proliferation of some specialized cells, suggesting that Cdk inhibitors are likely to produce certain toxicities by affecting specific cells. 3,[5][6][7] Nonetheless, Cdk4 inhibition may be effective to prevent Myc-induced skin tumors, 8 Rasinduced breast cancer 9 or K-Ras-induced non-small-cell lung carcinoma. 10 These results suggest that Cdk inhibition may be exploited in clinical settings taking into consideration the cellular context of the tumor and the pathogenic spectrum of their mutations.…”