The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3.

p53 mutations with single amino acid changes in cancer often lead to dominant oncogenic changes. Here, we have developed a mouse model of gain-of-function (GOF) p53-driven lung cancer utilizing conditionally active LSL p53-R172H and LSL K-Ras-G12D knock-in alleles that can be activated by Cre in lung club cells. Mutation of the p53 transactivation domain (TAD) (p53-L25Q/W26S/R172H) eliminating significant transactivation activity resulted in loss of tumorigenicity, demonstrating that transactivation mediated by or dependent on TAD is required for oncogenicity by GOF p53.

Mechanisms regulating DMTF1β/γ expression and their functional interplay with DMTF1α.

The cyclin D binding myb‑like transcription factor 1 (DMTF1), a haplo‑insufficient tumor suppressor gene, has 3 alternatively spliced mRNA isoforms encoding DMTF1α, β and γ proteins. Previous studies have indicated a tumor suppressive role of DMTF1α and the oncogenic activity of DMTF1β, while the function of DMTF1γ remains largely undetermined. In the present study, the mechanisms regulating DMTF1 isoform expression were investigated and the functional interplay of DMTF1β and γ with DMTF1α was characterized.

Survival of Lung Cancer Patients Dependent on the LOH Status for , , and .

Lung cancer is the leading cause of cancer deaths in the world, and accounts for more solid tumor deaths than any other carcinomas. The prognostic values of , , and p53-loss are unknown in lung cancer. We have conducted survival analyses of non-small cell lung cancer (NSCLC) patients from the University of Minnesota VA hospital and those from the Wake Forest University Hospital.

Aberrant Expression of p14 in Human Cancers: A New Biomarker?

The and genes are located on the locus, both showing tumor suppressive activity. ARF has been shown to monitor potentially harmful oncogenic signalings, making early stage cancer cells undergo senescence or programmed cell death to prevent cancer. Conversely, detects both aging and incipient cancer cell signals, and thus these two gene functions are different.

c-MYB and DMTF1 in Cancer.

The c-Myb gene encodes a transcription factor that regulates cell proliferation, differentiation, and apoptosis through protein-protein interaction and transcriptional regulation of signaling pathways. The protein is frequently overexpressed in human leukemias, breast cancers, and other solid tumors suggesting that it is a bona fide oncogene. c-MYB is often overexpressed by translocation in human tumors with t(6;7)(q23;q34) resulting in c-MYB-TCRβ in T cell ALL, t(X;6)(p11;q23) with c-MYB-GATA1 in acute basophilic leukemia, and t(6;9)(q22-23;p23-24) with c-MYB-NF1B in adenoid cystic carcinoma.

Translocations involving ETS family proteins in human cancer.

The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating certain gene transcriptions. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences.

Tumor suppression by the EGR1, DMP1, ARF, p53, and PTEN Network.

Recent studies have indicated that EGR1 is a direct regulator of tumor suppressors including TGFβ1, PTEN, and p53. The Myb-like transcription factor Dmp1 is a physiological regulator of the Arf-p53 pathway through transactivation of the promoter and physical interaction of p53. The promoter has binding sites for Egr proteins, and is a target for Dmp1.

Aberrant expression of ETS1 and ETS2 proteins in cancer.

The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating gene transcription. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences.

Aberrant expression of p16 in human cancers - a new biomarker?

The and genes are located in the same locus, both showing its tumor suppressive activity. ARF has been shown to detect potentially harmful oncogenic signals, making incipient cancer cells undergo senescence or apoptosis. INK4a, on the other hand, responds to signals from aging in a variety of tissues including islets of Langerhans, neuronal cells, and cancer stem cells in general.

Haploinsufficient tumor suppressor genes.

Haploinsufficiency of tumor suppressor genes (TSGs) indicates that the reduced levels of proteins in cells that lack one allele of the genomic locus results in the inability of the cell to execute normal cellular functions contributing to tumor development. Representative cases of haploinsufficient TSGs are and . Tumor development is significantly accelerated in both mice with homozygous and heterozygous gene deletion, with expression of the wild type allele in the latter.

Stabilization of the p53-DNA Complex by the Nuclear Protein Dmp1α.

We recently reported the existence of a physical interaction between the Myb-like transcription factor Dmp1 (Dmtf1) and p53 in which Dmp1 antagonized polyubiquitination of p53 by Mdm2 and promoted its nuclear localization. Dmp1 significantly stabilized p53-DNA complexes on promoters that contained p53-consensus sequences, which were either supershifted or disrupted with antibodies to Dmp1. Lysates from mice injected with doxorubicin showed that Dmp1 bound to p21, Bbc3, and Thbs1 gene regulatory regions in a p53-dependent fashion.

Clinical applications of mouse models for breast cancer engaging HER2/neu.

Human c-ErbB2 (HER2) has long been used as a marker of breast cancer (BC) for sub-categorization for the prediction of prognosis, and determination of therapeutic strategies. HER2 overexpressing BCs are more invasive/metastatic; but patients respond to monoclonal antibody therapy with trastuzumab or tyrosine kinase inhibitors, at least at early stages. To date, numerous mouse models that faithfully reproduce HER2(+) BCs have been created in mice.

Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu.

The human c-ErbB2 (HER2) gene is amplified in ∼20% of human breast cancers (BCs), but the protein is overexpressed in ∼30% of the cases indicating that multiple different mechanisms contribute to HER2 overexpression in tumors. It has long been used as a molecular marker of BC for subcategorization for the prediction of prognosis and determination of therapeutic strategies. In comparison to ER(+) BCs, HER2-positive BCs are more invasive, but the patients respond to monoclonal antibody therapy with trastuzumab or tyrosine kinase inhibitors at least at early stages.

Novel Molecular Markers for Breast Cancer.

The use of molecular biomarkers assures that breast cancer (BC) patients receive optimal treatment. Established biomarkers, such as estrogen receptor, progesterone receptor, HER2, and Ki67, have been playing significant roles in the subcategorization of BC to predict the prognosis and decide the specific therapy to each patient. Antihormonal therapy using 4-hydroxytamoxifen or aromatase inhibitors have been employed in patients whose tumor cells express hormone receptors, while monoclonal antibody to HER2 has been administered to HER2-positive BCs.

Aberrant splicing of the DMP1-ARF-MDM2-p53 pathway in cancer.

Alternative splicing (AS) of mRNA precursors is a ubiquitous mechanism for generating numerous transcripts with different activities from one genomic locus in mammalian cells. The gene products from a single locus can thus have similar, dominant-negative or even opposing functions. Aberrant AS has been found in cancer to express proteins that promote cell growth, local invasion and metastasis.

Aberrant Splicing of Estrogen Receptor, HER2, and CD44 Genes in Breast Cancer.

Breast cancer (BC) is the most common cause of cancer-related death among women under the age of 50 years. Established biomarkers, such as hormone receptors (estrogen receptor [ER]/progesterone receptor) and human epidermal growth factor receptor 2 (HER2), play significant roles in the selection of patients for endocrine and trastuzumab therapies. However, the initial treatment response is often followed by tumor relapse with intrinsic resistance to the first-line therapy, so it has been expected to identify novel molecular markers to improve the survival and quality of life of patients.

Transcription factors that interact with p53 and Mdm2.

The tumor suppressor p53 is activated upon cellular stresses such as DNA damage, oncogene activation, hypoxia, which transactivates sets of genes that induce DNA repair, cell cycle arrest, apoptosis, or autophagy, playing crucial roles in the prevention of tumor formation. The central regulator of the p53 pathway is Mdm2 which inhibits transcriptional activity, nuclear localization and protein stability. More than 30 cellular p53-binding proteins have been isolated and characterized including Mdm2, Mdm4, p300, BRCA1/2, ATM, ABL and 53BP-1/2.

Aberrant expression of cyclin D1 in cancer.

Cyclin D1 binds and activates cyclin-dependent kinases 4/6 (Cdk4/6) to phosphorylate the retinoblastoma (RB) family proteins, relieving E2F/DPs from the negative restraint of RB proteins and histone deacetylases. The cyclin D-Cdk4/6 complexes activate cyclin E/Cdk2 through titration of the Cdk inhibitors p21/p27. Cyclin E/Cdk2 further phosphorylates RBs, thereby activating E2F/DPs, and cells enter the S phase of the cell cycle.

DMP1β, a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer.

Our recent work has indicated that the DMP1 locus on 7q21, encoding a haplo-insufficient tumour suppressor, is hemizygously deleted at a high frequency in breast cancer. The locus encodes DMP1α protein, an activator of the p53 pathway leading to cell cycle arrest and senescence, and two other functionally undefined isoforms, DMP1β and DMP1γ. In this study, we show that the DMP1 locus is alternatively spliced in ∼30% of breast cancer cases with relatively decreased DMP1α and increased DMP1β expression.

Alterations of p63 and p73 in human cancers.

p53 and its related genes, p63 and p73 constitute the p53 gene family. While p53 is the most frequently mutated gene in human tumors, p63 and p73 are rarely mutated or deleted in cancers. Many studies have reported p63/p73 overexpression in human cancers while others showed that a loss of p63/p73 is associated with tumor progression and metastasis.

Dmp1α inhibits HER2/neu-induced mammary tumorigenesis.

Our recent study shows a pivotal role of Dmp1 in quenching hyperproliferative signals from HER2 to the Arf-p53 pathway as a safety mechanism to prevent breast carcinogenesis. To directly demonstrate the role of Dmp1 in preventing HER2/neu-driven oncogenic transformation, we established Flag-Dmp1α transgenic mice (MDTG) under the control of the mouse mammary tumor virus (MMTV) promoter. The mice were viable but exhibited poorly developed mammary glands with markedly reduced milk production; thus more than half of parous females were unable to support the lives of new born pups.

Cooperation between Dmp1 loss and cyclin D1 overexpression in breast cancer.

Cyclin D1 is a component of the core cell-cycle machinery and is frequently overexpressed in breast cancer. It physically interacts with the tumor suppressor Dmp1 that attenuates the oncogenic signals from Ras and HER2 by inducing Arf/p53-dependent cell-cycle arrest. Currently, the biological significance of Dmp1-cyclin D1 interplay in breast cancer has not been determined.

Recent progress in mouse models for tumor suppressor genes and its implications in human cancer.

Gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes (TSG) lead to cancer. In most human cancers, these mutations occur in somatic tissues. However, hereditary forms of cancer exist for which individuals are heterozygous for a germline mutation in a TSG locus at birth.

Positive and negative regulation of prostate stem cell antigen expression by Yin Yang 1 in prostate epithelial cell lines.

Prostate cancer is influenced by epigenetic modification of genes involved in cancer development and progression. Increased expression of Prostate Stem Cell Antigen (PSCA) is correlated with development of malignant human prostate cancer, while studies in mouse models suggest that decreased PSCA levels promote prostate cancer metastasis. These studies suggest that PSCA has context-dependent functions, and could be differentially regulated during tumor progression.

Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.

The transcription factor Dmp1 is a Ras/HER2-activated haplo-insufficient tumor suppressor that activates the Arf/p53 pathway of cell-cycle arrest. Recent evidence suggests that Dmp1 may activate p53 independently of Arf in certain cell types. Here, we report findings supporting this concept with the definition of an Arf-independent function for Dmp1 in tumor suppression.