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1. Strain-Specific Spontaneous and NNK-Mediated Tumorigenesis in Pten+/− Mice

Author

Mary Christine Hollander, Andria R. Balogh, Jaminelli Liwanag, Wei Han, Ritva Ilona Linnoila, Miriam R. Anver, and Phillip A. Dennis

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Pten is a negative regulator of the Akt pathway, and its inactivation is believed to be an etiological factor in many tumor types. Pten+/- mice are susceptible to a variety of spontaneous tumor types, depending on strain background. Pten+/- mice, in lung tumor-sensitive and -resistant background strains, were treated with a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether allelic Pten deletion can cooperate with NNK in carcinogenesis in lung or other tissues. In lung tumor-resistant C57BL/6 Pten+/- or +/+ mice, NNK treatment did not lead to any lung tumors and did not increase the incidence or severity of tumors previously reported for this strain. In contrast, in a lung tumor-susceptible pseudo-A/J strain, there was a dose-dependent increase in lung tumor size in Pten+/- compared with +/+ mice, although there was no increase in multiplicity. No other tumor types were observed in pseudo-A/J Pten+/- mice regardless of NNK treatment. Lung tumors from these Pten+/- mice had K-ras mutations, retained Pten expression and had similar Akt pathway activation as lung tumors from +/+ mice. Therefore, deletion of a single copy of Pten does not substantially add to the lung tumor phenotype conferred by mutation of K-ras by NNK, and there is likely no selective advantage for loss of the second Pten allele in lung tumor initiation.

Published
2008
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2. Hematopoietic cells from Gadd45a- and Gadd45b-deficient mice are sensitized to genotoxic-stress-induced apoptosis

Author

Barbara Hoffman, Arthur G. Balliet, Shiv K. Gupta, Mamta Gupta, Mary Christine Hollander, Albert J. Fornace, and Dan A. Liebermann

Subjects
Cancer Research, Ultraviolet Rays, Blotting, Western, Antineoplastic Agents, Apoptosis, Bone Marrow Cells, Genotoxic Stress, Biology, medicine.disease_cause, Mice, Genetics, medicine, Animals, Annexin A5, Molecular Biology, Cells, Cultured, Etoposide, Mice, Knockout, Gadd45, Cell Cycle, Daunorubicin, Intracellular Signaling Peptides and Proteins, Hematopoietic Stem Cells, Molecular biology, Antineoplastic Agents, Phytogenic, Haematopoiesis, Oxidative Stress, medicine.anatomical_structure, Retroviridae, Immunology, GADD45G, Ultraviolet Therapy, Bone marrow, Carcinogenesis, Genotoxicity, DNA Damage
Abstract

Gadd45a, gadd45b and gadd45g (Gadd45/MyD118/CR6) are genes that are rapidly induced by genotoxic stress. However, the exact function of Gadd45 proteins in the response of mammalian cells to genotoxic stress is unclear. Here, advantage was taken of gadd45a- and gadd45b-deficient mice to determine the role gadd45a and gadd45b play in the response of bone marrow (BM) cells to genotoxic stress. BM cells from gadd45a- and gadd45b-deficient mice were observed to be more sensitive to ultraviolet radiation chemotherapy (UVC), VP-16 and daunorubicin (DNR)-induced apoptosis compared to wild-type (wt) cells. The increased apoptosis in gadd45a- and gadd45b-deficient cells was evident also by enhanced activation of caspase-3 and poly-ADP-ribose polymerase cleavage and decreased expression of c-inhibitor of apoptotic protein-1, Bcl-2, Bcl-xL compared to wt cells. Reintroduction of gadd45 into gadd45-deficient BM cells restored the wt apoptotic phenotype. Both gadd45a- and gadd45b-deficient BM cells also displayed defective G2/M arrest following exposure to UVC and VP-16, but not to DNR, indicating the existence of different G2/M checkpoints that are either dependent or independent of gadd45. Taken together, these findings identify gadd45a and gadd45b as anti-apoptotic genes that increase the survival of hematopoietic cells following exposure to UV radiation and certain anticancer drugs.

Published
2005

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