Cyclin D1 is an essential mediator of apoptotic neuronal cell death.

Abstract

Many neurons in the developing nervous system undergo programmed cell death, or apoptosis. However, the molecular mechanism underlying this phenomenon is largely unknown. In the present report, we present evidence that the cell cycle regulator cyclin D1 is involved in the regulation of neuronal cell death. During neuronal apoptosis, cyclin D1‐dependent kinase activity is stimulated, due to an increase in cyclin D1 levels. Moreover, artificial elevation of cyclin D1 levels is sufficient to induce apoptosis, even in non‐neural cell types. Cyclin D1‐induced apoptosis, like neuronal apoptosis, can be inhibited by 21 kDa E1B, Bcl2 and pRb, but not by 55 kDa E1B. Most importantly, however, overexpression of the cyclin D‐dependent kinase inhibitor p16INK4 protects neurons from apoptotic cell death, demonstrating that activation of endogenous cyclin D1‐dependent kinases is essential during neuronal apoptosis. These data support a model in which neuronal apoptosis results from an aborted attempt to activate the cell cycle in terminally differentiated neurons.

Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

“…A compelling link between D cyclins and induction of apoptosis is provided by direct gain of cyclin D1 function studies in cell systems where overexpressed cyclin D promoted ectopic cell cycle transit (Hiyama and Reeves, 1999;Kranenburg et al, 1996;Sofer-Levi and Resnitzky, 1996). Mitigating this are the data in this report along with other investigations utilizing direct gain-and-loss of D cyclin function in lymphoid cells (Rhee et al, 1995;Warenius et al, 1996), cells from pancreatic carcinoma (Kornmann et al, 1997) and lung cancer cells (Driscoll et al, 1999).…”

“…The e ect of cyclin D1 can be pro-or anti-apoptotic depending on the proliferative and di erentiated state of the cell (reviewed in Han et al, 1999). Enforced expression of cyclin D1 in quiescent, post-mitotic neurons (Kranenburg et al, 1996), growth restricted ®broblasts (Sofer-Levi and Resnitzky, 1996), or irradiated ®broblasts (Pardo et al, 1996) stimulates cell cycle entry and leads to apoptosis. However, in cells ectopically expressing strong growth promoters, such as Myc and Ras, high levels of D-cyclins (cyclins D1, D2, and D3) rescue cells from apoptosis induced by dexamethasone (Rhee et al, 1995) or cytotoxic drugs (Warenius et al, 1996).…”

Cyclin D1 overexpression associates with radiosensitivity in oral squamous cell carcinoma

“…Cyclin D1 has an important role as a regulator of G1-S phase transition. Cells with high levels of cyclin D1 are generally thought to be more likely to undergo an apoptotic cell death in response to ionizing radiation [5,6,10]. Cyclin D1, on the other hand, binds to the CDK inhibitors p21 and p27 [14,15] and, on the other hand, induces expression of these CDK inhibitors [16][17][18].…”

“…The cyclin D1 gene is located on chromosome 11q13, a region frequently rearranged in many lymphomas and both amplified and overexpressed in carcinomas, including head and neck cancer [2][3][4]. Cyclin D1 is a nuclear protein that has been shown to be an important regulator of G1-S phase transition, and elevated levels of cyclin D1 induce apoptosis [5,6]. Furthermore, elevated cyclin D1 mRNA levels are associated with decreased survival of patients with cancers of breast, esophagus, and head and neck [7][8][9].…”

Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours

“…Promoter analysis of cyclins D2 and D3 revealed marked di erences in the control of gene expression following the stimulation by growth factors (Brooks et al, 1996). Moreover, various observations suggest that individual D-type cyclins have distinct functions in di erent cell types in addition to activating cdk4/6 (Ewen et al, 1993;Kato and Sherr, 1993;Lucibello et al, 1993;Sherr, 1993;Han et al, 1996;Kranenburg et al, 1996;Sofer-Levi and Resnitzki, 1996).…”