Expression and Mutation of the Tumor Suppressor Gene p53 in AIDS-Associated Kaposi's Sarcoma

Abstract

Alteration of the p53 gene is the most frequent event reported in human cancer, and p53 mutations have been observed in various neoplasms, including certain forms of skin cancer. Therefore, we postulated that p53 may also be involved in Kaposi's sarcoma associated with AIDS (AIDS-KS). Expression of the p53 gene was examined in freshly isolated tumor biopsy specimens from 15 patients with AIDS-KS. p53 mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in both the AIDS-KS tumors and in normal skin control samples. p53 protein was detected in 4 of the 15 AIDS-KS specimens by immunohistochemical staining. Single-strand conformation polymorphism analysis PCR-products (PCR-SSCP) was used for detection of mutations of the p53 gene. One of the p53 positive AIDS-KS samples showed mobilized shifts in exon 6 suggestive of a mutation. Sequencing data showed the mutation to be located in codon 210. We examined other mechanisms that could stabilize p53 protein. SV40 large T antigen and adenovirus E1B protein were not found in the AIDS-KS specimens. MDM2, a p53-binding protein, was also detected in five of the AIDS-KS specimens, two of which also contained p53-positive cells. These observations suggest that the tumor suppressor gene p53 may be involved in the pathogenesis of AIDS-KS.

Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter

“…kCYC was detected in the lung of kCYC ϩ/Ϫ mice and immunoprecipitated with anti-Cdk2, 4, and 6 antibodies ( Figure 2A and data not shown), proving that kCYC protein was expressed in our transgenic mice and that it was bound to cellular Cdk complexes, consistent with previous in vitro studies on kCYC. [21][22][23][24] We also demonstrated that kCYC/Cdk complexes were functionally active because they were able to phosphorylate both Rb and histone H1 ( Figure 2B-C), again consistent with previous in vitro studies. 24,25 Premature death and pleural effusion in kCYC ؉/؊ transgenic mice kCYC ϩ/Ϫ transgenic mice died prematurely starting at 3 weeks of age; approximately 80% of mice were dead by 6 months of age For personal use only.…”

“…It interacts with all types of cyclin-dependent kinases (Cdks), although it preferentially binds to Cdk6. [21][22][23][24] kCYC/Cdk6 complexes phosphorylate and inactivate both retinoblastoma (Rb) protein 24,25 and the Cdk inhibitor p27, 26,27 which leads to unregulated progression through the cell cycle. In the presence of normal p53 function, kCYC also sensitizes cells to undergo apoptosis, 24,28,29 whereas in the absence of p53, kCYC promotes cell survival.…”

Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Prolongs the Life Span of Primary Human Umbilical Vein Endothelial Cells

“…Thus, the role that kCYC plays in KS pathogenesis may be critically dependent upon whether p53 is damaged or lost within KS tumors. In this regard, studies examining p53 function in KS, although limited, suggest that p53 mutations are not common in KS tumors (29,36,60), unlike in many other human cancers.…”

Kaposi's Sarcoma-Associated Herpesvirus K-Cyclin Interacts with Cdk9 and Stimulates Cdk9-Mediated Phosphorylation of p53 Tumor Suppressor

“…However, the expression of p53 varies in different stages of KS progression. The expression of p53 was hardly detectable in the early stage of KS, but the percentage of p53-positive cells increased in the more advanced stage (2,18,34,45,55,62,71). Apparently, the absence of p53 results in a disadvantage for cells in controlling the aberrant proliferation that is induced by KSHV viral proteins, such as K-cyclin.…”