Molecular Mechanisms of Cellular Senescence and Oncogenesis in Human
Cells

My laboratory is investigating the molecular mechanisms of cellular senescence,   immortalization and oncogenesis in human cells. Senescence constitutes a permanent proliferation block. Cells must overcome senescence in order to become immortal and further undergo transformation. Several years ago, we discovered the biomarker of cellular senescence, which is extensively used to characterize the senescent phenotype of cells in culture and in organism. Currently, we are focusing on candidate genes that can bypass senescence, induce immortal phenotype, and cooperate with other oncogenes to transform human fibroblasts and human mammary epithelial cells (HMECs). In particular, we have identified a candidate oncogene Bmi-1, which induces telomerase in   HMECs. Its overexpression ultimately leads to immortalization of HMECs, and in cooperation with other oncogenes it can transform HMECs. We have also found that Bmi-1 is overexpressed in breast cancer cell lines and in invasive breast tumors. The enzyme telomerase is activated in majority of cancers including breast cancer. Telomerase and genes that activate telomerase are attractive candidate for various cancers including breast cancer. We are studying the molecular mechanisms of telomerase activation by Bmi-1 and aim to identify the cellular genes that are involved in telomerase induction by Bmi-1. Bmi-1 belongs to a group of transcriptional repressors known as polycomb group (PcG). These proteins maintain the repressive stage of chromatin. We are also studying the role of Bmi-1 related PcG proteins in senescence and oncogenesis. Our aim is to identify the target genes that are repressed by Bmi-1 and related polycomb proteins which are associated with breast cancer. In addition to studying the role of PcG proteins in oncogenesis, we also plan to study the role of PcG proteins and regulators of telomerase expression and telomere length in aging.  

Guo, W-J., Zeng, M.-S. Yadav, A., Song, L-B., Guo, B.-H, Band, V and G. P. Dimri. (2007). Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and downregulating Akt activity in breast cancer cells. Cancer Res. In Press.

Zhao, Y., Katzman, R.B., Delmolino, L.M., Bhat, I., Zhang, Y., Gurumurthy, C.B., Reddi, H.V., Solomon, A., Zeng, M.S., Kung, A., Ma, H., Gao, Q., Dimri, G., Stanculescu, A., Miele, L., Wu, L., Griffin, J.D., Wazer, D.E., Band, H. and V. Band. (2007). The notch regulator MamL1 interacts with p53 and functions as a coactivator. J. Biol. Chem. 282(16):11969-11981.

Kang, M.K., Kim, R.H., Kim, S.J., Yip, F.K., Shin, K.H., Dimri, G.P , Christensen, R., Han, T. And N.H. Park. (2007) Elevated Bmi- 1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival. Br. J. Cancer 96: 126-133.

Zhang, Y., Gurumurthy, C.B, Kim, J.H, Bhat, I., Gao, Q., Dimri, G. , Lee, S.W., Band, H and V. Band (2006). The human ortholog of Drosophila ecdysoneless protein interacts with p53 and regulates its function. Cancer Res. 66: 7167-7175.

Guo, W-J., Datta, S., Band, V. and G. P. Dimri (2007). Mel-18, a polycomb group protein regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins. Mol. Biol. Cell. 18: 536-546.

Nag, A., Germaniuk-Kurowaska, A., Dimri, M., Sassack, M., Gurumurthy, C.B., Gao, Q., Dimri, G., Band, H. and V. Band. (2007). An essential role of human ADA3 in p53 acetylation. J. Biol. Chem. 2007 282(12):8812-8820.

Dimri, M., Naramura, M., Duan, L., Chen, J., Cesar, O-Cava, Gengsheng, C.,Goswami, R., Fernandes, N., Gao, Q., Dimri, G.P. , Band, V. and H. Band (2007). Modeling breast cancer-associated c-Src and EGF receptor overexpression in human mammary epithelial cells: c-Src and EGFR cooperatively promote aberrant three-dimensional acinar structure and invasive behavior Cancer Res. 67(9):4164-4172.

R. Maurelli, S. Bondanza, L. Guerra, C. Abbruzzese, G. Dimri, M. Gellini, G. Zambruno, and E. Dellambra (2006). Inactivation of p16INK4a (inhibitor of cyclin-dependent kinase 4A) immortalizes primary human keratinocytes by maintaining cells in the stem cell compartment. FASEB J. Jun 5; [Epub ahead of print]

L-B. Song, M.-S. Zeng, W-T. Liao, L. Zhang, H-Y. Mo, W.-L. Liu, J-Y. Shao, Q-L Wu, M-Z. Li, Y-H Xia, L-W. Fu, W.-L. Huang, G. Dimri, V. Band, and Y-X Zeng (2006). Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. Cancer Res. 66: 6225-6232.

G.P. Dimri (2005). What has senescence got to do with cancer? Cancer Cell 7: 505-512.

G.P. Dimri, H. Band, and V. Band (2005). Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res. 7: 171-179.

G. Meng, Y. Zhao, A. Nag, M. Zeng, G. Dimri, Q. Gao, D.E. Wazer, R. Kumar, H. Band, and V. Band (2004). Human ADA3 binds to estrogen receptor (ER) and functions as a coactivator for ER- mediated transactivation. J. Biol. Chem. 279:54230-5440.

G. Dimri (2004). The Search for Biomarkers of Aging: Next Stop INK4a/ARF Locus. Sci Aging Knowledge Environ. Nov 03;2004(44):pe40.

K. Itahana, J. Campisi, and G. P. Dimri (2004). Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5: 1-10.

K. Itahana, Z. Ying, Y. Itahana, J.L. Martinez, C. Beausejour, J.L. Jacobs, M. van Lohuizen, V. Band, J. Campisi, and G. P. Dimri (2003). Control of replicative senescence in human fibroblast by the polycomb protein Bmi-1 and p16. Mol. Cell. Biol. 23: 389-401.

M. Zeng, A. Kumar, G. Meng, Q. Gao, G. Dimri, D. Wazer, H. Band, and V. Band (2002). HPV16 E6 oncoprotein inhibits RXR-mediated transactivation by targeting human ADA3 coactivator. J. Biol. Chem. 277: 45611-45618.

A. Kumar, Y. Zhao, G. Meng, M. Zeng, S. Srinivasan, Q. Gao, G. Dimri, G. Weber, D. Wazer, H. Band, and V. Band (2002). Human papilloma virus oncoprotein E6 inactivates the transcriptional coactivator human ADA3. Mol. Cell. Biol. 22: 5801-5812.

G.P. Dimri, J.L. Martinez, J.L. Jacobs, P. Keblusek, K. Itahana, M. van Lohuizen, J. Campisi, D.E. Wazer, and V. Band (2002). Bmi-1 oncogene induces telomerase and immortalizes human mammary epithelial cells. Cancer Res. 62: 4736-4745.

K. Itahana, G.P. Dimri, Y. Itahana, Y. Zou, E. Hara, P.Y. Desprez, and J. Campisi (2002). A role for p53 in maintaining and establishing quiescence growth arrest in human cells. J. Biol. Chem. 277:18206-18214.

B. Li, J. Goyal, S. Dhar, G.P. Dimri, E. Evron, S. Sukulmar, and V. Band (2001). CpG methylation in exon 3 as a basis for breast tumor specific loss of NES1 expression. Cancer Res. 61: 8014-8021.

K. Itahana, G.P. Dimri, and J. Campisi (2001). Regulation of cellular senescence by p53. Eur. J. Biochem. 268, 2784-2791.

G.P. Dimri, K. Itahana, M. Acosta, and J. Campisi (2000). Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor. Mol. Cell. Biol. 20, 273-285.

View all publications by publications by Goberdhan Dimri listed in the National Library of Medicine (PubMed).