Cytoplasmic retention of mutant tsp53 is dependent on an intermediate filament protein (Vimentin) scaffold

Klotzsche, Oliver; D, Etzrodt; Hohenberg, Heinz; Bohn, Wolfgang; Deppert, Wolfgang

doi:10.1038/sj.onc.1202155

Cited by 54 publications

(43 citation statements)

References 36 publications

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“…15 In accordance with observations in other cell systems, 16 p53 Val-135 in C6D10-p53 Val-135 cells exhibited an mt conformation at the restrictive temperature (Figure 1a; pAb240), and adopted the wt conformation upon shift to the permissive temperature (Figure 1a; pAb246). After shift to the permissive temperature, the steady-state level of p53 was reduced to a low, nearly physiological level, as shown by immunofluorescence (Figure 1b) and WB ( Figure 1c).…”

Section: C6d10-p53supporting

confidence: 89%

Cooperation between p53 and p130(Rb2) in induction of cellular senescence

et al. 2005

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To determine pathways cooperating with p53 in cellular senescence when the retinoblastoma protein (pRb)/p16INK4a pathway is defunct, we stably transfected the p16INK4a-negative C6 rat glioma cell line with a temperature-sensitive mutant p53. Activation of p53 induces a switch in pocket protein expression from pRb and p107 to p130(Rb2) and stalls the cells in late G1, early S-phase at high levels of cyclin E. Maintenance of the arrest depends on the functions of p130(Rb2) repressing cyclin A. Inactivation of p53 in senescent cultures restores the pocket proteins to initial levels and initiates progression into S-phase, but the cells fail to resume proliferation, likely due to DNA damage becoming apparent in the arrest and activating apoptosis subsequent to the release from p53-dependent growth suppression. The data indicate that p53 can cooperate selectively with p130(Rb2) to induce cellular senescence, a pathway that may be relevant when the pRb/p16INK4a pathway is defunct.

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Section: C6d10-p53supporting

confidence: 89%

Cooperation between p53 and p130(Rb2) in induction of cellular senescence

et al. 2005

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“…Besides mutational mechanisms, there are other ways in which p53 is sequestered to the cytoplasm, such as binding of wild-type p53 to other proteins such as mdm-2 15,16 or conformational changes of the wild-type protein caused by temperature and cytoskeletal anchorage. 17 Our data and their results indicate that accumulation of the p53 protein in the cytoplasm in colorectal cancer resulted not only from nuclear-excluded wild-type protein but also from the mutated type. The characteristics of p53 accumulated in the cytoplasm in different types of tumors may be different.…”

Section: Discussionmentioning

confidence: 49%

p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation

2001

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Previous studies have shown that nuclear p53 over-expression is an indicator of p53 mutations whereas cytoplasmic p53 accumulation is related to wild-type p53 in several kinds of tumors. Cytoplasmic p53 accumulation has been demonstrated to be an independent prognostic factor in colorectal adenocarcinomas. The purpose was to examine whether mutations occur in cases with p53 accumulated in the cytoplasm and whether there are any differences in the frequency and characteristics of p53 mutations in different staining patterns. In the present study, we identified p53 mutations using PCR single-strand conformation polymorphism (SSCP) and DNA sequencing in 75 primary colorectal adenocarcinomas with different staining patterns (negative, nucleus, cytoplasm, nucleus and cytoplasm). The results show that the frequency and nature of mutations in tumors with cytoplasmic p53 accumulation were similar to those with nuclear p53 expression. However, the tumors with accumulation in both the nucleus and cytoplasm demonstrated a higher mutation rate. We suppose that the role of cytoplasmic p53 accumulation in predicting prognosis in patients with colorectal cancer may be dependent on both mutational and non-mutational mechanisms. Wild-type p53 protein functions as a transregulator of genes involved in DNA synthesis, DNA repair and apoptosis. 1 Wild-type p53 is normally low. However, p53 that is inactivated through mutations, deletions or binding to other proteins results in p53 protein accumulation which can be detected by immunohistochemistry. 2 Over-expression of the p53 protein has been reported in approximately 50% of colorectal cancers. 3 The majority of investigators have focused on nuclear p53 expression and considered it as an indication of p53 gene mutation. Actually, p53 cytoplasmic accumulation is present in different types of tumors including colorectal cancer, 4 -7 breast cancer 5,8 and neuroblastoma. 8 However, the studies on these tumors showed that cytoplasmic p53 was associated with wild-type p53. 9,10 To our knowledge, investigators have not used DNA sequencing to investigate p53 mutations in human colorectal cancer tissue with cytoplasmic p53 over-expression. Several groups have shown that cytoplasmic p53 accumulation is associated with advanced tumor stage and is an independent prognostic factor in patients with colorectal cancer, whereas nuclear accumulation is not. 6,8,11 Further, the patients with p53-positive tumors in both the nucleus and cytoplasm had the most unfavorable outcome. 6 We previously found that cytoplasmic p53, but not nuclear p53, is associated with heat shock proteins in colorectal cancer. 12 These results indicate that the characteristics and roles of the subcellular localization of p53 protein may be different in controlling p53 function.In our study, we used PCR single-strand conformation polymorphism (SSCP) and DNA sequencing to evaluate p53 mutations with different patterns of p53 protein accumulation (negative, nucleus, cytoplasm, nucleus and cytoplasm) in 75 colorectal cancers from ...

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“…We propose that this theme can be enlarged to include the status of actin ®bres as well. In further support of the latter idea are the observations that disruption of actin by either heat or cytochalasin treatment (Rubtsova et al, 1998) also activates and stabilizes p53 (Klotzsche et al, 1998). In addition, it is noteworthy to list the proteins encoded by p53 regulated genes whose function is integral to the cytoskeletal architecture.…”

Section: Gip-17mentioning

confidence: 89%