Andrew B. Gladden

Expression of constitutively nuclear cyclin D1 in murine lymphocytes induces B-cell lymphoma

Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by overexpression of cyclin D1 due to the t(11;14) chromosomal translocation. While expression of cyclin D1 correlates with MCL development, expression of wild-type (WT) cyclin D1 transgene in murine lymphocytes is unable to drive B-cell lymphoma. As cyclin D1 mutants that are refractory to nuclear export display heighten oncogenicity in vitro compared with WT D1, we generated mice expressing FLAG-D1/T286A, a constitutively nuclear mutant, under the control of the immunoglobulin enhancer, Eμ. D1/T286A transgenic mice universally develop a mature B-cell lymphoma. Expression of D1/T286A in B lymphocytes results in S phase entry in resting lymphocytes and increased apoptosis in spleens of young premalignant mice. Lymphoma onset correlates with perturbations in p53/MDM2/p19Arf expression and with BcL-2 overexpression suggesting that alterations in one or both of these pathways may contribute to lymphoma development. Our results describe a cyclin D1-driven model of B-cell lymphomagenesis and provide evidence that nuclear-retention of cyclin D1 is oncogenic in vivo.

Location, Location, Location: The Role of Cyclin D1 Nuclear Localization in Cancer

The control of cell proliferation is crucial in maintaining cellular homeostasis and loss of this mechanism is a principle hallmark of cancer cells. A primary target of growth factor signaling is the cyclin D1‐dependent kinase (D1‐CDK4/6) whose activity promotes G1 phase progression by phosphorylating the retinoblastoma protein (Rb) along with related pocket proteins 107 and p130, relieving inhibition of E2F family transcription factors. Cyclin D1 accumulation is regulated at multiple levels including transcription, post‐translational activation and cellular localization throughout the cell cycle. While overexpression of cyclin D1 has been observed in a number of human cancers, mouse cancer models overexpressing D1 have fallen short of establishing a role for cyclin D1 in the initiation of malignant phenotypes suggesting an additional regulatory mechanism exists that prevents cyclin D1‐driven cancer. This article will present an overview of current data investigating the regulation of cyclin D1 nuclear localization and the prevalence of these aberrations in cancer. Finally, future avenues of research involving cyclin D1 cellular localization and its regulation in cancer will be addressed. J. Cell. Biochem.

Disruption of cyclin D1 nuclear export and proteolysis accelerates mammary carcinogenesis

Cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and polyubiquitination by SCFFBX4-αB crystallin. Inhibition of cyclin D1 proteolysis has been implicated as a causative factor leading to its overexpression in breast and esophageal carcinomas; however, the contribution of stable cyclin D1 to the genesis of such carcinomas has not been evaluated. We therefore generated transgenic mice wherein expression of either wild-type or a stable cyclin D1 allele (D1T286A) is regulated by MMTV-LTR. MMTV-D1T286A mice developed mammary adenocarcinomas at an increased rate relative to MMTV-D1 mice. Similar to human cancers that overexpress cyclin D1, D1T286A tumors were estrogen receptor-positive and exhibited estrogen-dependent growth. Collectively, these results suggest that temporal control of cyclin D1 subcellular localization and proteolysis is critical for maintenance of homeostasis within the mammary epithelium.

A central domain of cyclin D1 mediates nuclear receptor corepressor activity

Regulation of nuclear receptor activity is the focus of numerous ongoing studies to develop novel therapies for the treatment of hormone-related cancer. Although cyclin D1 functions to control the activity of several nuclear receptors, the region(s) of the protein responsible for such transcriptional comodulation remain poorly defined. Herein, we map the region of cyclin D1 required for binding and repression of the androgen receptor (AR) to a central, exclusively α-helical domain. Deletion of this domain disrupted AR binding and corepressor activity. Further investigations showed that this domain is sufficient for AR interaction and possesses the ability to bind histone deacetylase 3. Strikingly, overexpression of this repressor region attenuates cell cycle progression in prostatic adenocarcinoma cells. The requirement of this domain for nuclear receptor repression was conserved with respect to thyroid hormone receptor beta-1, whereas cyclin D1 activation of the estrogen receptor occurred independently of the central region. Together, these data identify a minimal repression module within cyclin D1 and demonstrate that the coactivator and corepressor functions of cyclin D1 are distinct. In addition, our data suggest that properties of the cyclin D1 central domain could be exploited to develop novel prostate cancer therapeutics.

Cell cycle progression without cyclin E/CDK2: Breaking down the walls of dogma

G1 is the phase of the cell cycle wherein the cell is responsive to growth factor-dependent signals. As such, G1 regulation is frequently disrupted in cancer through deregulation of cyclin/CDK activity; deregulation of G1 phase provides tumorigenic cells with a growth advantage. Cyclin E, the regulatory cyclin for CDK2, is considered a requisite regulator of G1 progression. Cyclin E is overexpressed in cancer, suggesting that cyclin E/CDK2 deregulation contributes to tumorigenesis. Two papers now challenge both the concept that cyclin E/CDK2 is a requisite component of the cell cycle machine and efforts to develop cyclin E/CDK2 inhibitors as antiproliferative therapeutics.

Loss of polarity alters proliferation and differentiation in low-grade endometrial cancers by disrupting Notch signaling

Cell adhesion and apicobasal polarity together maintain epithelial tissue organization and homeostasis. Loss of adhesion has been described as a prerequisite for the epithelial to mesenchymal transition. However, what role misregulation of apicobasal polarity promotes tumor initiation and/or early progression remains unclear. We find that human low-grade endometrial cancers are associated with disrupted localization of the apical polarity protein Par3 and Ezrin while, the adhesion molecule E-cadherin remains unchanged, accompanied by decreased Notch signaling, and altered Notch receptor localization. Depletion of Par3 or Ezrin, in a cell-based model, results in loss of epithelial architecture, differentiation, increased proliferation, migration and decreased Notch signaling. Re-expression of Par3 in endometrial cancer cell lines with disrupted Par3 protein levels blocks proliferation and reduces migration in a Notch dependent manner. These data uncover a function for apicobasal polarity independent of cell adhesion in regulating Notch-mediated differentiation signals in endometrial epithelial cells.