The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. These populations started expansion in neonatal mice and, upon malignant transformation, caused fatality at age between 3–11 months.
Here, we report rapid lymphoma development in Id 2/ Id 3 double knockout (L-DKO) mice caused by unchecked expansion of either invariant Natural Killer T (iNKT) cells, or a unique subset of innate-like, CD 1d-independent T cells. Although upregulation of Id proteins has been associated with a broad spectrum of tumors, recent studies have identified that ID 3 plays a tumor suppressor role in the development of Burkitt’s lymphoma in humans and Hepatosplenic T cell lymphomas in mice. Inhibitor of DNA binding ( ID) proteins, including ID 1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Li, Jia Roy, Sumedha Kim, Young-Mi Li, Shibo Zhang, Baojun Love, Cassandra Reddy, Anupama Rajagopalan, Deepthi Dave, Sandeep Diehl, Anna Mae Zhuang, Yuan ID 2 collaborates with ID 3 to suppress iNKT and innate-like tumors 1 Because Id family members inhibit various bHLH transcription factors, it is conceivable that the induced Id 1-3 would cooperatively modulate gene expressions in melanotrophs under CS conditions to induce hormone secretion. These results suggest that the decreased dopamine levels in the IL during CS induce Id 1-3 expressions in melanotrophs. Moreover, an in vitro study using primary cultured melanotrophs demonstrated a direct effect on Id 1-3 inductions by dopamine suppression. Administration of the dopamine D 2 receptor agonist bromocriptine prevented the inductions of Id 1-3 in the IL of CS rats, whereas application of the dopamine D 2 antagonist sulpiride induced significant expressions of Id 1-3 in the IL of normal rats. RT-PCR, Western blotting and in situ hybridization confirmed the significant inductions of Id 1, Id 2 and Id 3 in the IL of CS rats. Among the genes up-regulated under CS conditions, we focused on the inhibitor of DNA binding/differentiation ( Id) family of dominant negative basic helix-loop-helix (bHLH) transcription factors. Using microarray analysis, we identified several genes differentially expressed in the IL under CS conditions. In this study, we investigated the molecular basis for the changes that occur in melanotrophs during CS. In rats under continuous stress (CS) there is decreased hypothalamic dopaminergic innervation to the intermediate lobe (IL) of the pituitary gland, which causes hyperactivation and subsequent degeneration of melanotrophs in the IL.
Konishi, H Ogawa, T Nakagomi, S Inoue, K Tohyama, M Kiyama, H Id 1, Id 2 and Id 3 are induced in rat melanotrophs of the pituitary gland by dopamine suppression under continuous stress.