Chesnokova Vera, Kovacs Kalman, Castro Anna-Valeria, Zonis Svetlana, Melmed Shlomo
Cedars-Sinai Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90048, USA.
Mol Endocrinol. 2005 Sep;19(9):2371-9. doi: 10.1210/me.2005-0137. Epub 2005 May 26.
Pituitary tumor transforming gene (Pttg) is induced in pituitary tumors and associated with increased tumor invasiveness. Pttg-null mice do not develop tumors, but exhibit pituitary hypoplasia, whereas mice heterozygous for the retinoblastoma (Rb) deletion develop pituitary tumors with high penetrance. Pttg-null mice were therefore cross-bred with Rb+/- mice to test the impact of pituitary hypoplasia on tumor development. Before tumor development, Rb+/-Pttg-/- mice have smaller pituitary glands with fewer cycling pituitary cells and exhibit induction of pituitary p21 levels. Pttg silencing in vitro with specific short hairpin interfering RNA in AtT20 mouse corticotrophs led to a marked induction of p21 mRNA and protein levels, decreased RB phosphorylation, and subsequent 24% decrease in S-phase cells. Eighty-six percent of Rb+/-Pttg+/+ mice develop pituitary adenomas by 13 months, in contrast to 30% of double-crossed Rb+/-Pttg-/- animals (P < 0.01). Pituitary hypoplasia, associated with suppressed cell proliferation, prevents the high penetrance of pituitary tumors in Rb+/- animals, and is therefore a protective determinant for pituitary tumorigenesis.
垂体肿瘤转化基因（Pttg）在垂体肿瘤中被诱导表达，并与肿瘤侵袭性增加相关。Pttg基因敲除小鼠不发生肿瘤，但表现出垂体发育不全，而视网膜母细胞瘤（Rb）基因缺失的杂合子小鼠则具有高肿瘤发生率，会发生垂体肿瘤。因此，将Pttg基因敲除小鼠与Rb+/-小鼠进行杂交，以测试垂体发育不全对肿瘤发生的影响。在肿瘤发生之前，Rb+/-Pttg-/-小鼠的垂体较小，垂体细胞增殖较少，并表现出垂体p21水平的诱导。在AtT20小鼠促肾上腺皮质激素细胞中用特异性短发夹干扰RNA体外沉默Pttg导致p21 mRNA和蛋白水平显著诱导，RB磷酸化降低，随后S期细胞减少24%。86%的Rb+/-Pttg+/+小鼠在13个月时发生垂体腺瘤，相比之下，双杂交的Rb+/-Pttg-/-动物中这一比例为30%（P < 0.01）。与细胞增殖受抑制相关的垂体发育不全可防止Rb+/-动物垂体肿瘤的高发生率，因此是垂体肿瘤发生的一个保护决定因素。
