mcc111

Mathew C. Casimiro, PhD

Contact Dr. Casimiro

Kimmel Cancer Center
233 S. Tenth Street, Suite 1035
Philadelphia, PA 19107

(215) 503-9350
(215) 923-4498 fax

Education
PhD, University of Sunderland, United Kingdom
MSc, University of Sussex at Brighton, United Kingdom
BSc, University of Portsmouth, United Kingdom

Expertise & Research Interests

Cyclin D1 is a gatekeeper which controls exit from G1 state into S phase. It partners with the cyclin dependent kinases to promote phosphorylation of the retinoblastoma protein thus releasing the transcription factors of the E2F family to promote DNA synthesis. The cyclin D1 gene is amplified in approximately 30% of human breast adenocarcinomas, and the protein is reportedly overexpressed in 60 to 80% of all cases. In mice localized overexpression of cyclin D1 is sufficient to induce mammary tumors. We have recently described a novel function of cyclin D1 in controlling mitochondrial function and size. Mitochondrial activity assayed by Mitotracker staining was enhanced by genetic deletion or antisense or small interfering RNA to cyclin D1. Global gene expression profiling and functional analysis of mammary epithelium cell-targeted cyclin D1 antisense transgenics demonstrated that cyclin D1 inhibits mitochondrial activity and down regulates a key component of glycolysis, namely Hexokinase II. Thus in addition to regulating nuclear DNA synthesis, cyclin D1 also regulates mitochondrial function in vivo, coordinating metabolic substrate utilization within the cell. The implications this novel function of cyclin D1 has on normal cellular function and in cancer are currently being investigated.

Cyclin D1 also regulates transcription at the chromatin level by interacting with histone deacetylases and various transcription factors to regulate genes that contribute to differentiation and proliferation. Recently cyclin D1 promoter occupancy was assessed at high resolution, using ChIP-Seq, the global genomic footprint for cyclin D1. We identified 3, 222 regions (intervals) associated with cyclin D1, approximately 70% these intervals were within 10kb of 2, 840 genes with a high density located within 500bp of the transcriptional start point. We next interrogated the functional pathways associated with the genes bound by cyclin D1. One of the most enriched terms was cell division; most of the genes being involved in G2/M phase and cellular mitosis. Misregulation of genes that govern the mitotic phase often lead to chromosomal instability (CIN). Whether a cause or a consequence of tumorigenesis, CIN itself is recognized as promoting transformation, associated with poor prognosis and metastasis. Understanding the transcriptional role of cyclin D1 in promoting CIN is of considerable clinical importance since it is commonly misexpressed in breast, pancreatic, lung cancer and lymphoma. Cyclin D1 rescue of cyclin D1-/- MEFs induced CIN gene expression and cyclin D1 bound the promoters of genes governing CIN. Chromosomal aberrations were confirmed by spectral karyotyping and abnormalities in the mitotic process were confirmed by immunofluorescence. Mammary gland targeted cyclin D1 expression induced tumors with CIN and acute transgenic expression induced CIN in vivo.  On going work focuses on the contribution of CIN to the molecular mechanisms governing relatively early changes in tumor progression.

Keywords

Cyclin D1, mitochondrial function, Chromosomal Instability