Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression

Abstract

Cyclin D1 binds to the Cdk4 and Cdk6 to form a pRB kinase. Upon phosphorylation, pRB loses its repressive activity for the E2F transcription factor, which then activates transcription of several genes required for the transition from the G1- to S-phase and for DNA replication. The cyclin D1 gene is rearranged and overexpressed in centrocytic lymphomas and parathyroid tumors and it is amplified and/or overexpressed in a major fraction of human tumors of various types of cancer. Ectopic overexpression of cyclin D1 in fibroblast cultures shortens the G1 phase of the cell cycle. Furthermore, it has been demonstrated that introduction of an antisense cyclin D1 into a human carcinoma cell line, in which the cyclin D1 gene is amplified and overexpressed, causes reversion of the malignant phenotype. Thus, increased expression of cyclin D1 can play a critical role in tumor development and in maintenance of the malignant phenotype. However, it is insufficient to confer transformed properties on primary or established fibroblasts. In this review, we summarize the role of cyclin D1 on tumor development and malignant transformation. In addition, our chemical biology study to understand the regulatory mechanism of cyclin D1 transcription is also reviewed.

Figure 1

Functions of the cyclin D1 protein in tumor progression. Overexpression of cyclin D1 can confer tumor cells with enhanced malignancy through increases in anchorage‐independent growth and vascular endothelial growth factor (VEGF) production, and down‐regulation of Fas expression, leading to resistance to chemotherapeutic agents.

Figure 2

E2F‐targeted genes. The transcriptional activity of E2F‐1 is negatively regulated by the product of the retinoblastoma tumor suppressor gene (pRB) and is indirectly regulated by a specific cyclin, such as the D‐type cyclins and their associated kinases (Cdk4 and Cdk6). Fibroblast growth factor receptor‐1 (FGFR‐1) and FGFR‐2 represent a new class of genes targeted by E2F. Their expressions are increased at the level of transcription by the overexpression of cyclin D1.

Figure 3

Possible mechanism of tumor progression in Cyclin D1‐overexpressing tumor cells. Overexpression of cyclin D1 due to gene rearrangement, gene amplification or simply increased transcription can cooperate with basic fibroblast growth factor (bFGF), which is produced by stromal cells, to cause further progression of transformation in established fibroblasts through induction of increased expression of fibroblast growth factor receptor‐1 (FGFR‐1) and FGFR‐2.

Figure 4

Structure of leptomycin B.

Figure 5

Structures of protein phosphatase inhibitors.

Figure 6

Schematic representation of the primary structure of PP2Acα (human) showing a putative nuclear export signal (NES) sequence. PP2A is a holoenzyme composed of three subunits, the catalytic subunit (PP2A/C), the structural A subunit (also known as PR65), and the regulatory B subunit. We searched for a leucine‐rich sequence with conserved spacings and hydrophobicity that fits the criteria established for a NES in the primary amino acid sequences of these three subunits, and we found that a NES lies between 149 and 158 in human PP2Acα. Nuclear export signals are boxed.

Figure 7

Possible mechanism of leptomycin B (LMB)‐induced inhibition of cyclin D1 expression. (a) The phosphorylation of c‐Jun at Ser‐63 and Ser‐73 enables c‐Jun to activate the transcription of the AP‐1‐responsive cyclin D1 gene. (b) The nuclear accumulation of PP2A induced by LMB leads to sustained dephosphorylation of c‐Jun at Ser‐63, therefore reducing the transcription of the AP‐1‐responsive cyclin D1 gene.