Jeannette Philipp-Staheli

Publications (5)35.28 Total impact

• Source

  Available from: PubMed Central

  Article: Genetic variability of the envelope gene of Type D simian retrovirus-2 (SRV-2) subtypes associated with SAIDS-related retroperitoneal fibromatosis in different macaque species.

  Jeannette Philipp-Staheli, Taya Marquardt, Margaret E Thouless, A Gregory Bruce, Richard F Grant, Che-Chung Tsai, Timothy M Rose
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  ABSTRACT: D-type simian retrovirus-2 (SRV-2) causes an AIDS-like immune deficiency syndrome (SAIDS) in various macaque species. SAIDS is often accompanied by retroperitoneal fibromatosis (RF), an aggressive fibroproliferative disorder reminiscent of Kaposi's sarcoma in patients with HIV-induced AIDS. In order to determine the association of SRV-2 subtypes with SAIDS-RF, and study the evolution and transmission of SRV-2 in captive macaque populations, we have molecularly characterized the env gene of a number of SRV-2 isolates from different macaque species with and without RF. We sequenced the env gene from eighteen SRV-2 isolates and performed sequence comparisons and phylogenetic analyses. Our studies revealed the presence of six distinct subtypes of SRV-2, three of which were associated with SAIDS-RF cases. We found no association between SRV-2 subtypes and a particular macaque species. Little sequence variation was detected in SRV-2 isolates from the same individual, even after many years of infection, or from macaques housed together or related by descent from a common infected parent. Seventy-two amino acid changes were identified, most occurring in the larger gp70 surface protein subunit. In contrast to the lentiviruses, none of the amino acid variations involved potential N-linked glycosylation sites. Structural analysis of a domain within the gp22/gp20 transmembrane subunit that was 100% conserved between SRV-2 subtypes, revealed strong similarities to a disulfide-bonded loop that is crucial for virus-cell fusion and is found in retroviruses and filoviruses. Our study suggests that separate introductions of at least six parental SRV-2 subtypes into the captive macaque populations in the U.S. have occurred with subsequent horizontal transfer between macaque species and primate centers. No specific association of a single SRV-2 subtype with SAIDS-RF was seen. The minimal genetic variability of the env gene within a subtype over time suggests that a strong degree of adaptation to its primate host has occurred during evolution of the virus.
  Virology Journal 02/2006; 3:11. · 2.34 Impact Factor
• Article: Genetic variability of the envelope gene of Type D simian retrovirus-2 (SRV-2) subtypes associated with SAIDS-related retroperitoneal fibromatosis in different macaque species

  Jeannette Philipp-Staheli, Taya Marquardt, Margaret Thouless, Bruce A Gregory, Richard Grant, Che-Chung Tsai, Timothy Rose
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  ABSTRACT: Abstract Background D-type simian retrovirus-2 (SRV-2) causes an AIDS-like immune deficiency syndrome (SAIDS) in various macaque species. SAIDS is often accompanied by retroperitoneal fibromatosis (RF), an aggressive fibroproliferative disorder reminiscent of Kaposi's sarcoma in patients with HIV-induced AIDS. In order to determine the association of SRV-2 subtypes with SAIDS-RF, and study the evolution and transmission of SRV-2 in captive macaque populations, we have molecularly characterized the env gene of a number of SRV-2 isolates from different macaque species with and without RF. Results We sequenced the env gene from eighteen SRV-2 isolates and performed sequence comparisons and phylogenetic analyses. Our studies revealed the presence of six distinct subtypes of SRV-2, three of which were associated with SAIDS-RF cases. We found no association between SRV-2 subtypes and a particular macaque species. Little sequence variation was detected in SRV-2 isolates from the same individual, even after many years of infection, or from macaques housed together or related by descent from a common infected parent. Seventy-two amino acid changes were identified, most occurring in the larger gp70 surface protein subunit. In contrast to the lentiviruses, none of the amino acid variations involved potential N-linked glycosylation sites. Structural analysis of a domain within the gp22/gp20 transmembrane subunit that was 100% conserved between SRV-2 subtypes, revealed strong similarities to a disulfide-bonded loop that is crucial for virus-cell fusion and is found in retroviruses and filoviruses. Conclusion Our study suggests that separate introductions of at least six parental SRV-2 subtypes into the captive macaque populations in the U.S. have occurred with subsequent horizontal transfer between macaque species and primate centers. No specific association of a single SRV-2 subtype with SAIDS-RF was seen. The minimal genetic variability of the env gene within a subtype over time suggests that a strong degree of adaptation to its primate host has occurred during evolution of the virus.
  Virology Journal. 01/2006;
• Article: Distinct roles for p53, p27Kip1, and p21Cip1 during tumor development.

  Jeannette Philipp-Staheli, Kyung-Hoon Kim, Denny Liggitt, Kay E Gurley, Gary Longton, Christopher J Kemp
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  ABSTRACT: Mutations in p53 and reduced expression of the Cdk inhibitor p27Kip1 are frequently observed in a wide variety of human cancers, but it is not known whether alterations in these tumor suppressors interact to influence tumor progression. To address this, we measured tumor latency and spectrum in p53 and p27 single and compound mutant mice. p53-/- (null) mice developed T-cell lymphomas and soft-tissue sarcomas, while p27-/- mice developed adenomas of the pituitary and lung, but with much longer latency. The latency for tumor development in p53-/- p27-/- and p53-/- p27+/- compound mutant mice was significantly reduced, by 15-30%, compared to single mutant p53-/- mice. The tumor spectrum in the compound mutants was similar to that of p53-/- mice, and additional tumors of diverse histotypes. In tumors from p53-/- mice, p27 protein levels were reduced to a greater extent than were mRNA levels, indicating that p27 is downregulated in tumors at the transcriptional as well as post-transcriptional levels. In contrast, mice deficient in another Cdk inhibitor p21Cip1, which is also a transcriptional target and effector of p53, showed only a marginal increase in tumor predisposition in response to ENU treatment. Thus, downregulation of p27 is a common feature in p53-/- tumors. Germline deletion of one or both alleles of p27 accelerates tumor development and associated mortality in p53-/- mice, indicating potent synergy between loss of p27 and p53. Although p21 is functionally similar to both p53 and p27, it plays a lesser role in tumor suppression. These results further highlight the highly cooperative nature of p27 and its central role in tumor suppression.
  Oncogene 02/2004; 23(4):905-13. · 6.37 Impact Factor
• Article: Pathway-specific tumor suppression. Reduction of p27 accelerates gastrointestinal tumorigenesis in Apc mutant mice, but not in Smad3 mutant mice.

  Jeannette Philipp-Staheli, Kyung-Hoon Kim, Shannon R Payne, Kay E Gurley, Denny Liggitt, Gary Longton, Christopher J Kemp
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  ABSTRACT: Expression of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) is frequently reduced in human colorectal cancer, and this correlates with poor patient prognosis. To clarify the role of p27 in gastrointestinal (GI) cancer, we measured p27 expression, as well as the effect of germline deletion of p27, in 3 different mouse models of GI neoplasia. p27 expression was frequently reduced in GI tumors arising in 1,2-dimethylhydrazine (DMH) treated mice, and in Apc mutant Min/+ mice, but not in GI tumors arising in Smad3 mutant mice. Germline deletion of p27 resulted in accelerated tumor development and increased tumor cell proliferation in both DMH treated and Min/+ mice, but not in Smad3 mutant mice. p27 deficiency also led to increased adenoma to adenocarcinoma progression. These results indicate that reduction of p27 cooperates with mutations in Apc but not in Smad3 during GI tumorigenesis. Thus, tumor suppression by p27 is contingent on the specific oncogenic pathway that drives tumor development.
  Cancer Cell 06/2002; 1(4):355-68. · 26.57 Impact Factor
• Article: p27Kip1: Regulation and Function of a Haploinsufficient Tumor Suppressor and Its Misregulation in Cancer

  Jeannette Philipp-Staheli, Shannon R. Payne, Christopher J. Kemp
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  ABSTRACT: A major function of p27, also known as Kip1, is to bind and inhibit cyclin/cyclin-dependent kinase complexes, thereby blocking cell cycle progression. As p27 operates at the heart of the cell cycle, it is perhaps not surprising that it is emerging as a key player in multiple cell fate decisions including proliferation, differentiation, and cell death. The central role of p27 makes it important in a variety of disease processes that involve aberrations in cellular proliferation and other cell fates. Most notable among these processes is neoplasia. A large number of studies have reported that p27 expression is frequently downregulated in human tumors. In most tumor types, reduced p27 expression correlates with poor prognosis, making p27 a novel and powerful prognostic marker. In addition to these practical implications, murine and tissue culture models have shown that p27 is a potent tumor suppressor gene for multiple epithelially derived neoplasias. Loss of p27 cooperates with mutations in several oncogenes and tumor suppressor genes to facilitate tumor growth, indicating that p27 may be a “nodal point” for tumor suppression. In contrast to most tumor suppressor genes studied to date, which are recessive at the cellular level, p27 is haploinsufficient for tumor suppression. The fact that tumor suppression by p27 is critically dependent on the absolute level of p27 expression indicates that p27 acts as a rheostat rather than as an on/off switch to control growth and neoplasia.
  Experimental Cell Research.