GREM1

Official Full Name

nuclear receptor subfamily 3 group C member 1

Organism

Homo sapiens

GeneID

2908

Background

This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

Synonyms

GR; GCR; GRL; GCCR; GCRST;

Protein Sequence

MSRTAYTVGALLLLLGTLLPAAEGKKKGSQGAIPPPDKAQHNDSEQTQSPQQPGSRNRGRGQGRGTAMPGEEVLESSQEALHVTERKYLKRDWCKTQPLKQTIHEEGCNSRTIINRFCYGQCNSFYIPRHIRKEEGSFQSCSFCKPKKFTTMMVTLNCPELQPPTKKKRVTRVKQCRCISIDLD

Open

Approved Drug

Clinical Trial Drug

Discontinued Drug

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Detailed Information

GREM1, or Gremlin 1, is a protein-coding gene that plays a crucial role in various biological processes. It belongs to the DAN (Cerberus and Dan) family of bone morphogenetic protein (BMP) antagonists. These antagonists, including GREM1, feature a C-terminal cystine knot with an eight-membered ring structure, typical of the BMP antagonist family. As an antagonist, GREM1 functions primarily by binding to BMPs, inhibiting their signaling pathways. BMPs, essential for regulating tissue differentiation, organogenesis, and body patterning, are crucial during early developmental stages.

First found in 1997 from transfected rat fibroblasts, GREM1 was called DRM (down-regulated in v-mos-transfected cells). Highly conserved across species, it codes for a cysteine-rich protein. Over time, further research has shown GREM1's participation in many processes including organ development, mesodermal differentiation, and cancer progression.

Biological Functions of GREM1

By blocking BMP signaling, GREM1 acts as a BMP antagonist. Usually, BMPs attach to cell membrane receptors, hence starting a series of intracellular processes controlling gene expression, development, and differentiation. GREM1 stops the receptor activation and disturbs the signaling cascade when it binds to BMPs. Various developmental processes, including kidney and limb creation, depend on this function.

Apart from its BMP-opposing role, GREM1 has been shown to affect other cellular processes. Overexpression of GREM1 in mesangial cells, for example, might trigger the ERK1/2 pathway, hence encouraging cell proliferation and extracellular matrix buildup. GREM1 may reestablish signaling pathways disturbed by damage in kidney cells exposed to toxins such as aristolochic acid, therefore guarding against phenotypic alterations and fibrosis. Moreover, via interacting with vascular endothelial growth factor receptors, GREM1 has been linked to angiogenesis, which helps to provide tumor blood supply and spread.

GREM1 and Tumorigenesis

Studies have shown GREM1's two functions in cancer. At first, GREM1 was thought to be a tumor suppressor. Research revealed it was downregulated in cancer cells; lower expression corresponded with cancer advancement. In breast cancer, for instance, lower GREM1 expression was linked to the onset of metastases. Recent studies, meantime, indicate that GREM1 might encourage cancer development in some malignancies.

GREM1 expression is increased in colorectal cancer and linked to carcinogenesis. Research has shown that via stimulating the TGF-\u03b2 signaling pathway, GREM1 drives epithelial-mesenchymal transition (EMT), a mechanism facilitating the spread of cancer cells and metastasis. GREM1 is also connected to familial colon cancer, where gene alterations correspond to higher vulnerability. Moreover, in pancreatic cancer, high GREM1 expression has been connected to a worse prognosis; its deletion has been connected to increased migration and proliferation of tumor cells.

Figure 1 illustrates the role of GREM1 in various cancers, highlighting its expression levels, effects on tumor progression, and potential as a diagnostic marker. Figure 1. Mechanism diagram of GREM1 in breast cancer. (Zhu D, et al., 2023)

Role of GREM1 in Specific Cancers

GREM1's role in breast cancer is particularly significant. Elevated levels of GREM1 in breast cancer tissues correlate with poor prognosis. In estrogen receptor-negative tumors, GREM1 enhances tumor cell proliferation and invasiveness by activating the EGFR pathway. GREM1's influence on tumor development and spread in colorectal cancer is clear. In patients, especially those with advanced-stage illness, increased GREM1 expression is linked to a worse prognosis. A key component in the course of colorectal cancer is the function of the protein in promoting EMT and affecting the development of metastatic lesions. Moreover, GREM1 is seen as a possible therapeutic target as its opposing actions on BMP signaling may be used to control tumor development.

In pancreatic cancer as well, GREM1 expression is related to cancer cell change. Loss of GREM1 may push epithelial cells to a more aggressive mesenchymal phenotype, therefore encouraging metastasis. GREM1, on the other hand, is not uniformly harmful in every cancer setting. Its increased expression in some studies is linked to improved prognoses because of its role in angiogenesis, a vital tumor development mechanism.

Therapeutic Implications and Future Research

Given GREM1's participation in many malignancies, it presents a possible therapeutic target. For example, in certain tumors, blocking GREM1 might prevent its pro-tumorigenic actions; in other settings, increasing its expression would return normal cellular function. Targeted treatments might seek to alter GREM1 levels either by directly blocking its interaction with BMPs or by affecting its expression in certain tumor microenvironments.

Furthermore, GREM1's function in the tumor immunological microenvironment is a developing field of research. Research indicates that its expression in the stroma of cancers affects immune cell infiltration, hence possibly affecting immunotherapy. Moreover, the finding of GREM1 as a pro-angiogenic element opens fresh paths for directing blood flow to tumors, a key driver of metastasis and tumor development.

References:

Chen S, Lei L, Li Z, et al. Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-β-mediated Smad2/3 phosphorylation. Exp Mol Med. 2022;54(4):518-530.
Zhu D, Zhao D, Wang N, et al. Current status and prospects of GREM1 research in cancer (Review). Mol Clin Oncol. 2023;19(3):69. Published 2023 Jul 19. doi:10.3892/mco.2023.2665.

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