Reviewing once more the c-myc and Ras collaboration

Abstract

The c-myc is a proto-oncogene that manifests aberrant expression at high frequencies in most types of human cancer. C-myc gene amplifications are often observed in various cancers as well. Ample studies have also proved that c-myc has a potent oncogenicity, which can be further enhanced by collaborations with other oncogenes such as Bcl-2 and activated Ras. Studies on the collaborations of c-myc with Ras or other genes in oncogenicity have established several basic concepts and have disclosed their underlying mechanisms of tumor biology, including "immortalization" and "transformation". In many cases, these collaborations may converge at the cyclin D1-CDK4 complex. In the meantime, however, many results from studies on the c-myc, Ras and cyclin D1-CDK4 also challenge these basic concepts of tumor biology and suggest to us that the immortalized status of cells should be emphasized. Stricter criteria and definitions for a malignantly transformed status and a benign status of cells in culture also need to be established to facilitate our study of the mechanisms for tumor formation and to better link up in vitro data with animal results and eventually with human cancer pathology.

Cyclin-dependent kinase 4 may be expressed as multiple proteins and have functions that are independent of binding to CCND and RB and occur at the S and G2/M phases of the cell cycle

“…1). The K112E mutation of CCND1, which abolishes the ability to activate CDK4 or CDK6, 6 attenuated the effect of CCND1 on CDK4 expression, although the attenuation varied among cell lines (Fig. 1).…”

“…Although some cyclins such as CCND1 and CCNE1 6,12 have been known to have functions that are independent of their partner CDKs, so far none of the CDK members has been known to function independently of a cyclin or of its kinase activity. In this study we provide, for the first time, evidence showing the existence of such mechanisms for CDK4 in some situations.…”

“…; they are also required for the assembling of the CCND-CDK4/6 complex but inhibit the kinase activity. 5,6 All CDK proteins share 3 common domains that are crucial for their binding to cyclins and inhibitors and for their kinase activity, i.e., (1) the ATP binding sequence and (2) the PSTAIRE domain, both at the N terminus, as well as (3) the kinase sequence in the middle region (Fig. 1).…”

“…One group includes p21cip1 and p27kip1, which help in assembling cyclin-CDK complex and internalizing the complex into the nucleus when they are present as a single molecule, but which inhibit the kinase activity when more molecules are present, i.e., overexpressed. 5,6 The other group is specific for CCND-CDK4/6 and includes p16ink4a (p16), p15ink4b, p18, etc. ; they are also required for the assembling of the CCND-CDK4/6 complex but inhibit the kinase activity.…”

TP53 and C-MYC Co-Alterations – A Hallmark of Oral Cancer Progression / SIMULTANA ALTERACIJA TP53 I C-MYC GENA – OBELEŽJE PROGRESIJE ORALNIH KARCINOMA

“…Namely, H-ras is usually induced by EGFR, which mediates extracellular mitogenic stimuli. Downstream event of Ras activation may actually be induction of cycD1 and promotion of cell replication (22). Ras activates cycD1 promoter via an AP-1 like sequence (23) and achieves predominant CycD1 nuclear localization.…”