White Martyn K, Skowronska Anna, Gordon Jennifer, Del Valle Luis, Deshmane Satish L, Giordano Antonio, Khalili Kamel
Center for Neurovirology, Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19122, USA.
Anticancer Res. 2006 Nov-Dec;26(6B):4079-92.
JC virus (JCV) is a polyomavirus that causes progressive multifocal leukoencephalopathy (PML) in humans and is highly oncogenic in experimental animals. Transgenic mice with JCV T-antigen develop cerebellar tumors, which resemble human medulloblastomas, containing two distinct cell subpopulations, T-antigen positive and negative. In T-negative clones, a novel mutant p53 was detected (p53(mt)).
We have compared p53(mt) to wild-type p53 (p53wt) in p53-null cells.
p53(mt) had lost the transcriptional transactivation activity of p53(wt), and unlike p53(wt), partially localized to the cytoplasm. Unlike mutant p53 from many human cancers, p53(mt) did not show a gain of function or a dominant negative phenotype. Adenovirus expressing p53(wt) but not p53(mt) inhibited cell growth and induced apoptosis of p53-null cells.
During the course of tumor evolution of the JCV T-antigen mouse medulloblastoma, a mutation occurred that inactivated p53 allowing tumor progression even in the absence of continued T-antigen expression.
JC病毒（JCV）是一种多瘤病毒，可导致人类进行性多灶性白质脑病（PML），并且在实验动物中具有高度致癌性。携带JCV T抗原的转基因小鼠会发生小脑肿瘤，类似于人类髓母细胞瘤，其中包含两个不同的细胞亚群，即T抗原阳性和阴性亚群。在T阴性克隆中，检测到一种新型突变型p53（p53(mt)）。
我们在p53基因缺失的细胞中比较了p53(mt)与野生型p53（p53wt）。
p53(mt)丧失了p53(wt)的转录反式激活活性，并且与p53(wt)不同，部分定位于细胞质中。与许多人类癌症中的突变型p53不同，p53(mt)未表现出功能获得或显性负性表型。表达p53(wt)而非p53(mt)的腺病毒抑制了p53基因缺失细胞的生长并诱导其凋亡。
在JCV T抗原小鼠髓母细胞瘤的肿瘤演变过程中，发生了一种使p53失活的突变，即使在没有持续T抗原表达的情况下也能使肿瘤进展。
