Structure and inducible regulation of the human MET promoter.

Gambarotta, Giovanna; Pistoi, Sergio; Giordano, Silvia; Comoglio, Paolo M.; Santoro, Claudio

doi:10.1016/s0021-9258(18)99954-0

Cited by 47 publications

(8 citation statements)

References 42 publications

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“…The expression of this gene has been considered, so far, mainly restricted to epithelial tissues (Prat et al, 1991a;Di Renzo et al, 1991). We recently identified in the c-MET promoter, among other consensus sequences for transcription factors, a GATA consensus motif (Gambarotta et al, 1994). The GATA-1 transcription factor is the first characterized member of a multigene family considered to be of major importance in the establishment and maintenance of the erythroid phenotype (Martin et ai., 1989).…”

Section: Discussionmentioning

confidence: 99%

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Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors.

Galimi

Bonsi

et al. 1994

The Journal of Cell Biology

126

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Abstract. Hepatocyte growth factor (HGF) is a mesenchymal derived growth factor known to induce proliferation and "scattering" of epithelial and endothelial ceils. Its receptor is the tyrosine kinase encoded by the c-MET protooncogene. Here we show that highly purified recombinant HGF stimulates hemopoietic progenitors to form colonies in vitro. In the presence of erythropoietin, picomolar concentrations of HGF induced the formation of erythroid burst-forming unit colonies from CD34-positive cells purified from human bone marrow, peripheral blood, or umbilical cord blood. The growth stimulatory activity was restricted to the erythroid lineage. HGF also stimulated the formation of multipotent CFU-GEMM colonies. This effect is synergized by stem cell factor, the ligand of the tyrosine kinase receptor encoded by the c-KIT protooncogene, which is active on early hemopoietic progenitors. By flow cytometry analysis, the receptor for HGF was found to be expressed on the cell surface in a fraction of CD34 ÷ progenitors. Moreover, in situ hybridization experiments showed that HGF receptor mRNA is highly expressed in embryonic erythroid cells (megaloblasts). HGF mRNA was also found to be produced in the embryonal liver. These data show that HGF plays a direct role in the control of proliferation and differentiation of erythroid progenitors, and they suggest that it may be one of the long-sought mediators of paracrine interactions between stromal and hemopoietic cells within the hemopoietic microenvironment.

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Section: Discussionmentioning

confidence: 99%

“…We recently cloned the promoter region of the HGF receptor gene (c-MET). Interestingly, a GATA-1 consensus sequence was found within 300 bp upstream from the transcription start site (Gambarotta et al, 1994). The GATA motif is known to identify genes preferentially expressed during erythroid differentiation (Martin et al, 1989).…”

mentioning

confidence: 99%

Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors.

Galimi

Bonsi

et al. 1994

The Journal of Cell Biology

126

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“…This raises the possibility that epigenetic modifications of MET may lead to the result that MACC1 cannot transcriptionally regulate MET in PC. Third, MACC1 is not the only regulator of MET, and there are many proteins other than MACC1 that can directly regulate MET expression (e.g., HIF1, SP1, AP1, and Ets-1) [ 38 – 41 ], suggesting that MACC1 may not be a predominant regulator of MET in pancreatic cancer. Similar to our result, Sueta A et al reported that MACC1 cannot activate MET and that MACC1 is not a major regulator of MET in breast cancer [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

MACC1 promotes pancreatic cancer metastasis by interacting with the EMT regulator SNAI1

et al. 2022

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Metastasis is the dominant cause of cancer-related mortality. Metastasis-associated with colon cancer protein 1 (MACC1) has been proven to play a critical role in cancer metastasis. However, the prometastatic role of MACC1 in regulating the pancreatic cancer (PC) metastatic phenotype remains elusive. Here, we report that MACC1 is highly expressed in The Cancer Genome Atlas (TCGA) and tissue microarray (TMA) and identified as a good indicator for poor prognosis. Overexpression or knockdown of MACC1 in PC cells correspondingly promoted or inhibited pancreatic cancer cell migration and invasion in a MET proto-oncogene receptor tyrosine kinase (MET)-independent manner. Notably, knockdown of MACC1 in PC cells markedly decreased the liver metastatic lesions in a liver metastasis model. Mechanistically, MACC1 binds to the epithelial-mesenchymal transition (EMT) regulator snail family transcriptional repressor 1 (SNAI1) to drive EMT via upregulating the transcriptional activity of SNAI1, leading to the transactivation of fibronectin 1 (FN1) and the trans-repression of cadherin 1 (CDH1). Collectively, our results unveil a new mechanism by which MACC1 drives pancreatic cancer cell metastasis and suggest that the MACC1-SNAI1 complex-mediated mesenchymal transition may be a therapeutic target in pancreatic cancer.

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“…It should be noted that a large dataset often restricts their analyses to protein-coding regions, overlooking important regulatory regions crucial for gene expression. The inducible nature of the MET promoter was previously described and its importance in tumor biology was established [ 149 , 150 , 151 ]. Thus, alterations affecting the MET promoter should not be disregarded: re-analyses of TCGA dataset showed a remarkable decrease in promoter methylation in cancer patients, a synonym for transcription activation and MET overexpression ( Figure 3 E).…”

Section: Genetic Alterations Of Met : the Peak Of ...mentioning

confidence: 99%

“…Moreover, the increased protein intensity is not necessarily a synonym for MET amplification and ‘addiction’. Because of the inducible nature of the MET promoter [ 149 , 150 , 151 ], high-MET-protein levels may be transient due to changes in the tumor microenvironment (e.g., hypoxia, ionizing radiation, cytotoxic reagents, described as ‘expedience’ in [ 3 ]). Indeed, post hoc analyses of some clinical trials illustrate this issue; patients with a gene copy number gain of MET > 4 exhibited the uppermost progression-free survival [ 92 ].…”

Section: Patient Stratification: a Key For Success In Targeted Therapiesmentioning

confidence: 99%

An Observatory for the MET Oncogene: A Guide for Targeted Therapies

Altintas,

Comoglio

2023

Cancers

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The MET proto-oncogene encodes a pivotal tyrosine kinase receptor, binding the hepatocyte growth factor (HGF, also known as scatter factor, SF) and governing essential biological processes such as organogenesis, tissue repair, and angiogenesis. The pleiotropic physiological functions of MET explain its diverse role in cancer progression in a broad range of tumors; genetic/epigenetic alterations of MET drive tumor cell dissemination, metastasis, and acquired resistance to conventional and targeted therapies. Therefore, targeting MET emerged as a promising strategy, and many efforts were devoted to identifying the optimal way of hampering MET signaling. Despite encouraging results, however, the complexity of MET’s functions in oncogenesis yields intriguing observations, fostering a humbler stance on our comprehension. This review explores recent discoveries concerning MET alterations in cancer, elucidating their biological repercussions, discussing therapeutic avenues, and outlining future directions. By contextualizing the research question and articulating the study’s purpose, this work navigates MET biology’s intricacies in cancer, offering a comprehensive perspective.

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Structure and inducible regulation of the human MET promoter.

Cited by 47 publications

References 42 publications

Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors.

Hepatocyte growth factor induces proliferation and differentiation of multipotent and erythroid hemopoietic progenitors.

MACC1 promotes pancreatic cancer metastasis by interacting with the EMT regulator SNAI1

An Observatory for the MET Oncogene: A Guide for Targeted Therapies

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