p53 downstream target genes and tumor suppression: a classical view in evolution

Rozan, Laura M.; El‐Deiry, Wafik S.

doi:10.1038/sj.cdd.4402058

Cited by 100 publications

(88 citation statements)

References 100 publications

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“…This broad effect is not surprising, because large-T is expected to mediate its action by inhibition of the p53 and Rb family of tumor suppressors. Large-T binding stabilizes p53, and the transformed cells should thus contain large amounts of functionally inactive p53 (16,17). Accordingly, our RNA-seq data show a 2.2-fold increase in p53 mRNA levels upon large-T transformation, as also confirmed on the protein level (Fig.…”

Section: Sv40 Transformation Causes Dedifferentiation and Massive Chasupporting

confidence: 55%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The transformation of normal cells to malignant, metastatic tumor cells is a multistep process caused by the sequential acquirement of genetic changes. To identify these changes, we compared the transcriptomes and levels and distribution of proteins in a fourstage cell model of isogenically matched normal, immortalized, transformed, and metastatic human cells, using deep transcriptome sequencing and immunofluorescence microscopy. The data show that ∼6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interestingly, the majority of these genes are down-regulated, linking malignant transformation to dedifferentiation. The up-regulated genes are mainly components that control cellular proliferation, whereas the down-regulated genes consist of proteins exposed on or secreted from the cell surface. As many of the identified gene products control basic cellular functions that are defective in cancers, the data provide candidates for follow-up studies to investigate their functional roles in tumor formation. When we further compared the expression levels of four of the identified proteins in clinical cancer cohorts, similar differences were observed between benign and cancer cells, as in the cell model. This shows that this comprehensive demonstration of the molecular changes underlying malignant transformation is a relevant model to study the process of tumor formation.C ancer development is a multistep process where genetic changes are accumulated, thus progressively transforming cells into a cancerous phenotype (1, 2). Over the last decades, numerous investigators have studied the underlying molecular mechanisms for malignant transformation. This has resulted in many models that explain the development of a malignant phenotype of human cells, for instance the "hallmarks of cancer" by Hanahan and Weinberg (3,4).With new technologies for deep sequencing, novel opportunities to study the underlying molecular events leading to cancers have emerged. A large number of investigations have analyzed mutations occurring in tumors, such as the analysis of mRNA expression, microRNA expression, and DNA copy number in a large number of tumors in the Cancer Genome Atlas (5). Similarly, the Human Protein Atlas project (6) studies human cancers using a proteome-wide collection of antibodies, resulting in publicly available immunohistochemistry images covering 20 different human cancer types.An interesting approach to studying the molecular mechanisms underlying cancer is to use an isogenically matched cell model in which normal cells are progressively transformed into malignant cells. There are several studies where genetic elements such as oncogenes have been introduced to different types of cells in an accumulative order as an attempt to mimic the natural steps of transformation (7,8). One such cell model is the fourstage model based on BJ fibroblasts developed by the Weinberg group, in which primary fibroblast cells were immortalized with telomerase reverse transcriptase (...

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Section: Sv40 Transformation Causes Dedifferentiation and Massive Chasupporting

confidence: 55%

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Danielsson

Skogs

Huss

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…1 Active p53 is subject to a complex series of post-translational modifications that markedly influence the expression of p53. 2 Thus, different enzymes which act upstream of p53 can inhibit or enhance p53 activity, which in turn results in inhibition or activation of downstream p53 target genes.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

Rokhlin¹,

Scheinker²,

Taghiyev³

et al. 2008

Cancer Biology & Therapy

140

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We investigated whether knocking down AR expression effects apoptosis after treatment with different apoptosis-inducing agents. We found that siRNA AR (si-AR) significantly decreased apoptosis induced by topoisomerase inhibitors doxorubicin (DOX) and camptothecin (Campt). It is known that DNA double-strand break inducing agents leads to activation (phosphorylation) of p53 that in turn regulates the expression of a variety of apoptosis-related genes including microRNA(miR)-34a and 34b/c. We found that DOX induced five phosphorylation sites of p53 (Ser15, 20, 37, 46 and 392); all of these sites were inhibited by si-AR. Subsequently we identified three kinases, SPAK, MDC1 and CaMKII that are under AR control and two of them, MDC1 and CaMKII, apparently participate in p53 upstream events that resulted in p53 inhibition. Using qPCR we showed that the level of miR-34a increased by 3-fold after DOX, but no increase was found with si-AR. MiR-34c expression increased 27 fold after DOX and only by 2.7 times with si-AR. It appears that AR-dependent inhibition of p53 resulted in suppression of miR-34a and -34c expression. Importantly, DOX did not induce miR-34 in LNCaP grown in an androgen free medium or in AR-negative prostate cancer cell lines, DU145 and PC3. To directly investigate the role of miR-34 in DOX-mediated apoptosis, we transfected cells with anti-miR-34 oligonucleotides or with miR-34. We found that inhibition of individual miR-34, either 34a or 34c, or forced overexpression of miR-34a or miR-34c did not modulate DOX-mediated apoptosis. Only simultaneous inhibition or forced overexpression of both miR-34 resulted in modulation of DOX-mediated apoptosis. Taken together, our data indicate that cooperation between miR-34a and 34c plays an important role in AR-dependent p53-mediated apoptosis in prostate cancer.

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“…18 The tumor suppressor p53 causes cell cycle arrest or apoptosis in response to DNA damage and other forms of stress. [35][36][37] The ability to localize into the nuclei is essential for p53 to act as a transcription factor. The modification of the subcellular distribution of p53 represents an important regulatory mechanism.…”

Section: Subcellular Location Of Hpv-11e6 Proteinmentioning

confidence: 99%

Two different HPV-11E6 fusion proteins trap p53 in the cytoplasm and induce apoptosis

Sun

Zhang²,

Lei³

et al. 2008

Cancer Biology & Therapy

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Mucosal high risk human papillomaviruses (HPVs) have been shown to be the major cause of cervical cancer. However, the reason why the low risk HPVs only cause proliferative but non-invasive lesions of infected epithelia remains elusive. Because p53 interacts with high risk HPVs E6 and plays a very important role in carcinogenesis, it is assumed that low risk HPVs E6 might interact with p53 in a different pattern. We used mammalian green fluorescent protein (GFP) tagged and polyhistidine (His) tagged proteins expression systems to express HPV-11E6 fusion proteins in wild-type (wt) p53 cell lines, such as 293T and MCF-7 cells to trace the traffic and location of E6s and p53. We showed that: (1) Following transfection, HPV-11E6 was predominantly expressed in the cytoplasm; (2) Using immunocytochemistry and Western blotting, endogenous wt p53 was shown to be trapped in cytoplasm by HPV-11E6 expression. (3) Apoptosis was increased in HPV-11E6 expressed cells. In conclusion, the entrapment of endogenous wt p53 in cytoplasm by the low risk HPV-11E6 may be one of the reasons why low risk HPV is not able to induce malignant transformation.

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p53 downstream target genes and tumor suppression: a classical view in evolution

Cited by 100 publications

References 100 publications

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

Two different HPV-11E6 fusion proteins trap p53 in the cytoplasm and induce apoptosis

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