Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

Kalo, Eyal; Buganim, Yosef; Shapira, Keren E.; Besserglick, Hilla; Goldfinger, Naomi; Weisz, Lilach; Stambolsky, Perry; Henis, Yoav I.; Rotter, Varda

doi:10.1128/mcb.00374-07

Cited by 70 publications

(57 citation statements)

References 49 publications

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“…In contrast, p53 R312Q mutation does not positively regulate migration of human endometrial cancer cells (25). p53 R175H mutation was shown to inhibit the migration of the H1299 lung cancer cell line when its RII was down-regulated and TGF-␤/Smad signaling was repressed (26). Here, we focused on the p53 DNA-binding domain mutations, which have been reported as the majority of p53 mutations in human breast and prostate cancer cell lines (43).…”

Section: Discussionmentioning

confidence: 99%

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Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Lin

Yang

et al. 2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

“…For example, in human endometrial cancer cells, the p53 R213Q mutation does not promote cell migration (25). As shown in another study using the H1299 cell line, p53 R175H negatively regulates cell migration when TGF-␤/Smad signaling is repressed (26). At present, the cellular context for mp53 to exert its oncogenic activity is underexplored.…”

mentioning

confidence: 98%

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Lin

Yang

et al. 2011

Journal of Biological Chemistry

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“…The FGF response is multifactorial and multigenic, as revealed by recent genome-wide transcriptomic screens (Branney et al, 2009). Interestingly, although Smads cooperate with wild-type p53 to promote developmental processes, they also cooperate with mutant p53, which often accumulates in human cancers (Adorno et al, 2009;Kalo et al, 2007). The Smadmutant p53 complex represses TGFBR2 transcription, leading to the induction of pro-metastatic genes.…”

Section: Regulatory Mechanisms Of Smad Transcriptional Co-factorsmentioning

confidence: 99%

The regulation of TGFβ signal transduction

2009

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Transforming growth factor  (TGF) pathways are implicated in metazoan development, adult homeostasis and disease. TGF ligands signal via receptor serine/threonine kinases that phosphorylate, and activate, intracellular Smad effectors as well as other signaling proteins. Oligomeric Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGF family members. Signaling is modulated by negative-feedback regulation via inhibitory Smads. We review here the mechanisms of TGF signal transduction in metazoans and emphasize events crucial for embryonic development. IntroductionThe human transforming growth factor  (TGF) family consists of 33 members, most of which encode dimeric, secreted polypeptides that control developmental processes, ranging from gastrulation and body axis asymmetry to organ-specific morphogenesis and adult tissue homeostasis (reviewed by Derynck and Miyazono, 2008). In addition to TGFs, this family includes the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins and nodal. The TGF family is conserved throughout metazoan evolution. At the cellular level, TGF family members regulate cell growth, differentiation, adhesion, migration and death, in a developmental context-dependent and cell type-specific manner. For example, TGF more often inhibits, but sometimes also stimulates, cell proliferation (reviewed by Yang and Moses, 2008). Furthermore, nodal signaling sometimes inhibits, whereas BMP promotes, cell differentiation, as in stem cells (Watabe and Miyazono, 2009). As TGF ligands act multifunctionally in numerous tissue types, they also play complex roles in various human diseases, ranging from autoimmune to cardiovascular diseases and cancer (reviewed by Gordon and Blobe, 2008;Massagué, 2008).Here we review the core components of the TGF family and their signaling engines, as part of a Minifocus in this issue on TGF signaling (see Box 1), and discuss emerging concepts concerning the regulatory mechanisms of TGF pathways at the receptor, cytoplasmic and nuclear level. We also highlight recent discoveries that are of particular developmental relevance. The TGF familyThe development of the axes and the asymmetry of the animal body depends on the localized action of extracellular signals, such as the Wnt, nodal and BMP ligands. Gradients of these ligands, their extracellular regulators and the competence of receptors in responding cells, play important roles during tissue morphogenesis (Affolter and Basler, 2007;Smith and Gurdon, 2004). TGF family members also contribute to tissue patterning and are important regulators of stem cell self-renewal and differentiation (see Box 2) (De Robertis and Kuroda, 2004;Watabe and Miyazono, 2009).The TGF morphogens include numerous secreted and conserved polypeptides (Table 1), which emerged at the onset of multicellular (metazoan) life (Huminiecki et al., 2009). Structurally, this family is characterized by a specific three-dimensional fold and by a conser...

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“…Rotter and co-workers 22 recently described the cross talk between mutant p53 and transforming growth factor TGFB1 signaling pathway. TGFB1 is known to have a critical role in preventing the initiation and progression of cancer.…”

Section: Mutant P53 Properties and Activitiesmentioning

confidence: 99%

Recent advances in p53 research: an interdisciplinary perspective

et al. 2008

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The TP53 gene is one of the most studied genes in human cancer. In recent years, considerable interest was focused on mutant p53, the abnormal protein product of TP53 somatic or germline alleles with missense mutations that often accumulate in cancer cells. There is now compelling experimental evidence that many mutations can exert mutant-specific, gain-of-function effects by perturbing the regulation of expression of multiple genes. This notion is supported by the observation that targeted mutant p53 expression enhances the formation of specific cancers in the mouse even in the absence of wild-type p53 expression. In addition, clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies. These correlations imply that alteration of p53 function is critical in shaping gene expression patterns in cancer. Finally, progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are reviewed. New opportunities for translational research for improving cancer detection, prognosis, prevention and therapy based upon the integration of this knowledge are described.

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Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II

Cited by 70 publications

References 49 publications

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

The regulation of TGFβ signal transduction

Recent advances in p53 research: an interdisciplinary perspective

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