Education:

• BS, 1996: Milia University, Delhi, India
• MS, 1998: Hamdard University, Delhi, India
• PhD 2003: Hamdard University, Delhi, India

Current Research:

Our research involves regulatory mechanisms of the Dmp1-Arf-p53 pathway and how it is disrupted in human cancer. Dmp1 is a Myb-like transcription factor that transmits oncogenic Ras-Raf signaling and causes p19Arf- p53-dependent cell cycle arrest in primary cells. Both Dmp1^-/- and Dmp1^+/- mice are prone to tumor development, especially adenocarcinomas including breast cancer when left untreated or when they are neonatally treated with carcinogen. Also our preliminary findings have indicated critical roles of Dmp1 in normal mammary gland development. Mice lacking Dmp1 have abnormal breast phenotype with little lobuloalveolar development with very less milk in their ducts. This is supported by our evidence of GeneChip Microarray and immunohistochemistry data for the EGFR ligands, amphiregulin and EGF. They were significantly downregulated in the mammary glands of Dmp1^-/- mice as compared to Dmp1^+/+ mice. HER2 is a trans-membrane glycoprotein that belongs to the EGF receptor protein tyrosine kinases. HER2 is overexpressed in ~30% of breast tumors, primarily due to gene amplification, and is associated with very poor prognosis of patients. We recently found that HER2 overexpression selectively activates both the Dmp1 and Arf promoters, suggesting the specific roles of the Dmp1-Arf pathway in breast cancer prevention. It has been reported that cyclin D1 is a critical target in MMTV-cyclin D1- and MMTV-ras-induced breast carcinogenesis. The human Cyclin D1 gene is amplified in ~15% of breast cancers and is associated with shorter survival of patients. On the other hand, the Cyclin D1 protein is overexpressed in >50% of human breast cancers and Cyclin D1 overexpression without gene amplification has been reported to be a favorable prognostic factor of breast cancer. We recently reported that Dmp1 and cyclin D1 collaborates to activate the Arf promoter to neutralize the oncogenic effects of cyclin D1. Our recent data show that both Dmp1^-/- and Dmp1^+/- mouse mammary epithelial cells are resistant to cyclin D1-induced cell cycle arrest in culture. The Dmp1 promoter is repressed by overexpression of E2Fs and physiological mitogens. We have also found that the Dmp1 promoter was activated by a classical NF-κB activator tumor necrosis factor α, but repressed by treatment of cells with non-classical NF-κB activators, anthracyclins and UV-C. p65 and other subsets of NF-κB proteins were bound to the Dmp1 promoter following anthracyclin/UV-C treatment of rodent fibroblasts. The amount of Dmp1 bound to the Arf promoter decreased significantly upon anthracyclin treatment. Both Dmp1^-/-and Arf^-/-cells showed resistance to anthracyclin induced cell death compared to wild-type cells; non-immortalized p65-knockdown cells were much more sensitive. Thus, the Dmp1-Arf pathway is repressed by p65 in response to genotoxic stress, which implicates a novel mechanism of p53 inactivation by NF-κB.

Figure Legend: Critical role of Dmp1 in Ras-Arf-p53 signaling. Arf is induced by potentially oncogenic signals stemming from overexpression of oncogenes such as c-Myc, E2F-1, and activated Ras. This quenches inappropriate mitogenic signaling by diverting incipient cancer cells to undergo p53-dependent and independent growth arrest or cell death. Arf expression is repressed by a number of nuclear proteins, such as Bmi1, Twist, Tbx, and Pokemon. Dmp1 directly binds and activates the Arf promoter, induces cell cycle arrest in Arf-dependent fashion. Both Dmp1-null and heterozygous mice show hypersensitivity to develop tumors in response to carcinogen DMBA and γ-irradiation. This phenotype could be explained by the inactivation of Arf-Mdm2-p53 pathway in the absence of the functional Dmp1 protein, although it is possible that Dmp1 has other targets than Arf. D-type cyclins inhibit Dmp1’s transcriptional activity in Cdk-independent fashion when E2Fs do not bind to the same promoter; however, D-cyclins cooperate with Dmp1 to activate the Arf promoter. The Dmp1 promoter is efficiently activated by the oncogenic Ras-Raf-MEK-ERK-Jun pathway. The induction of Arf by oncogenic Ras is largely dependent on Dmp1. The Dmp1 transcription is repressed by physiological mitogenic signaling as well as by overexpression of E2F proteins. We recently reported that the Dmp1-Arf pathway was inhibited by NF-κB proteins in response to genotoxic stress signaling.

Publications:

Sugiyama T, Taneja P, Frazier DP, Kendig RD, Morgan RL, Matise LA, Lagedrost SJ, Inoue K. Oncogenic and non-oncogenic signaling pathways that regulate Dmp1 (Dmtf1) (review). Clinical Medicine: Oncology 2008; 2: 209-19.

Inoue K, Sugiyama T, Taneja P, Morgan RL, Frazier DP.  Emerging roles of DMP1 in lung cancer (review).  Cancer Res 2008 Jun 15;68(12):4487-90.

Sugiyama T, Frazier DP, Taneja P, Morgan RL, Willingham MC,  Inoue K.  The role of Dmp1 and its future in lung cancer diagnostics.  Expert Rev Mol Diagn 2008, in press.

Mallakin A, Sugiyama T, Taneja P, Matise LA, Frazier DP, Choudhary M, Hawkins GA, D'Agostino RB Jr, Willingham MC, Inoue K. Mutually exclusive inactivation of DMP1 and ARF/p53 in lung cancer. Cancer Cell, 2007 Oct;12(4):381-94.

Taneja P, Mallakin A, Matise LA, Frazier DP, Choudhary M, Inoue K.  Repression of Dmp1 and the Arf transcription by anthracyclins: critical roles of the NF-kappaB subunit p65. Oncogene. 2007 Nov 22;26(53):7457-66.

Taneja P, Frazier DP, Sugiyama T, Lagedrost S, Inoue K. Control of cellular physiology by transcription factors E2F and their roles in carcinogenesis. Research Signpost. 2007. Review. [in press.]

Mallakin A, Taneja P, Matise LA, Willingham MC, Inoue K. Expression of Dmp1 in specific differentiated, nonproliferating cells and its regulation by E2Fs. Oncogene. 2006 Dec 14;25(59):7703-13.

Shukla Y, Taneja P, Arora A, Sinha N. Mutagenic potential of mancozeb in Salmonella Typhimurium. J Env Pathol Toxicol Oncol 2004, 23: 294-302.

Taneja P, Arora A, Shukla Y. Antimutagenic effects of black tea in the Salmonella Typhimurium reverse mutation assay. Asian Pac J Cancer Prev 2003, 4:193-198.

Shukla Y, Arora A, Taneja P. Antigenotoxic potential of certain dietary constituents. Teratog Carcinog Mutagen 2003, 23: 323-335.

Shukla Y, Taneja P. Anticarcinogenic effect of black tea on pulmonary tumors in Swiss albino mice. Cancer Lett. 2002,176: 137-141.

Shukla Y, Arora A, Taneja P. Antimutagenic potential of curcumin on chromosomal aberrations in Wistar rats. Mutat Res. 2002, 515:197-202.

Shukla Y, Taneja P. Antimutagenic effect of garlic extract on chromosomal aberrations. Cancer Lett. 2002,176: 31-36.

Shukla Y, Taneja P. Mutagenic evaluation of cypermethrin in mouse dominant lethal assay. J Env Pathol Toxicol Oncol 2002, 21: 259-265.

Shukla Y, Taneja P. Mutagenic evaluation of deltamethrin using rodent dominant lethal assay. Mutat Res. 2000. 467: 119-127.

Shukla, Y, Taneja, P. Antimutagenic effect of black tea extract using rodent dominant lethalmutation assay. Toxicology 2001 Nov 30;168: 269-274.