PROM1

Official Full Name

prominin 1

Organism

Homo sapiens

GeneID

8842

Background

This gene encodes a pentaspan transmembrane glycoprotein. The protein localizes to membrane protrusions and is often expressed on adult stem cells, where it is thought to function in maintaining stem cell properties by suppressing differentiation. Mutations in this gene have been shown to result in retinitis pigmentosa and Stargardt disease. Expression of this gene is also associated with several types of cancer. This gene is expressed from at least five alternative promoters that are expressed in a tissue-dependent manner. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

Synonyms

RP41; AC133; CD133; MCDR2; STGD4; CORD12; PROML1; MSTP061;

Protein Sequence

MALVLGSLLLLGLCGNSFSGGQPSSTDAPKAWNYELPATNYETQDSHKAGPIGILFELVHIFLYVVQPRDFPEDTLRKFLQKAYESKIDYDKPETVILGLKIVYYEAGIILCCVLGLLFIILMPLVGYFFCMCRCCNKCGGEMHQRQKENGPFLRKCFAISLLVICIIISIGIFYGFVANHQVRTRIKRSRKLADSNFKDLRTLLNETPEQIKYILAQYNTTKDKAFTDLNSINSVLGGGILDRLRPNIIPVLDEIKSMATAIKETKEALENMNSTLKSLHQQSTQLSSSLTSVKTSLRSSLNDPLCLVHPSSETCNSIRLSLSQLNSNPELRQLPPVDAELDNVNNVLRTDLDGLVQQGYQSLNDIPDRVQRQTTTVVAGIKRVLNSIGSDIDNVTQRLPIQDILSAFSVYVNNTESYIHRNLPTLEEYDSYWWLGGLVICSLLTLIVIFYYLGLLCGVCGYDRHATPTTRGCVSNTGGVFLMVGVGLSFLFCWILMIIVVLTFVFGANVEKLICEPYTSKELFRVLDTPYLLNEDWEYYLSGKLFNKSKMKLTFEQVYSDCKKNRGTYGTLHLQNSFNISEHLNINEHTGSISSELESLKVNLNIFLLGAAGRKNLQDFAACGIDRMNYDSYLAQTGKSPAGVNLLSFAYDLEAKANSLPPGNLRNSLKRDAQTIKTIHQQRVLPIEQSLSTLYQSVKILQRTGNGLLERVTRILASLDFAQNFITNNTSSVIIEETKKYGRTIIGYFEHYLQWIEFSISEKVASCKPVATALDTAVDVFLCSYIIDPLNLFWFGIGKATVFLLPALIFAVKLAKYYRRMDSEDVYDDVETIPMKNMENGNNGYHKDHVYGIHNPVMTSPSQH

Open

Disease

Acute myeloid leukaemia, Brain cancer, Colorectal cancer, Liver cancer, Ovarian cancer, Pancreatic cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

The PROM1 gene is located on human chromosome 4p15.32, spanning approximately 20 kb and containing 29 exons and 28 introns. PROM1 encodes the ~120 kDa pentaspan transmembrane glycoprotein CD133. Transcription of PROM1 is regulated by at least five tissue-specific promoters, producing multiple alternatively spliced isoforms. CD133 features characteristic extracellular N-glycosylated domains and two large extracellular loops, which enable it to localize preferentially to membrane protrusions such as microvilli and ciliary bases. Through cholesterol binding, CD133 forms specialized lipid raft microdomains that contribute to apical membrane topology. Subcellular localization varies dynamically: in neural stem cells, CD133 is enriched at the ciliary base; in retinal photoreceptors, at the base of the outer segment; and in epithelial cells, at apical microvilli. This spatial specificity underlies critical developmental functions, such as regulating photoreceptor disc morphogenesis, with CD133 deficiency leading to structural disorganization of photoreceptors.

Figure 1. Topological model of Prominin-1 (CD133), showing its five transmembrane domains and extracellular loops; "aa" denotes amino acids. (Devis-Jauregui L, et al., 2019)

Molecular Functions and Signaling

Beyond structural roles, CD133 functions as a signaling regulator. It interacts with key molecules in the Wnt/β-catenin pathway, including GSK3β and β-catenin, modulating nuclear translocation and transcriptional activity. In neural stem cells, CD133 interacts with Notch and Hedgehog pathway components to inhibit differentiation and maintain stemness. This “stem cell guardian” role is hijacked in tumors: in glioma, CD133 enhances cancer stem cell self-renewal and therapy resistance via RET-mediated MAPK/Akt signaling. CD133 expression is finely tuned post-transcriptionally; for example, microRNA-200b targets PROM1’s 3′UTR, promoting mRNA degradation and reducing CD133 levels, which is essential for maintaining epithelial differentiation.

Physiological Roles and Pathological Mechanisms

Physiologically, CD133 contributes to tissue development and homeostasis. In retinal development, CD133 acts as a scaffold for photoreceptor disc formation. Loss-of-function mutations in PROM1 cause autosomal recessive cone-rod dystrophy (CRD), leading to central vision loss and photoreceptor degeneration. Recent studies identified frameshift mutations (e.g., c.2321delC, p.A774Vfs*2) that reduce CD133 stability, alter subcellular localization, and activate autophagy, highlighting a novel pathogenic mechanism. In the nervous system, CD133 regulates asymmetric division of neural stem cells, determining progenitor fate and influencing neurogenesis.

In cancer, CD133 serves as a cancer stem cell marker. In pancreatic cancer, PROM1 expression correlates with stem cell-associated genes (EPCAM, POU5F1, CD24, CD44, CXCR4) and is linked to poor differentiation, advanced TNM stage, lymph node metastasis, and reduced survival. Glioma studies show that CD133 knockdown decreases cell invasion, supporting its role in promoting malignancy. CD133’s pathological effects are disease-specific: in hereditary retinal disorders, misfolded CD133 triggers ER stress and apoptosis, while in tumors, it maintains stemness, promotes epithelial-mesenchymal transition (EMT), and enhances drug efflux, contributing to therapy resistance. Interestingly, in some cancers, CD133 shows context-dependent effects: in renal clear cell carcinoma, higher CD133 expression may indicate better prognosis, whereas soluble CD133 fragments in gastric cancer can inhibit angiogenesis.

Clinical Relevance and Disease Spectrum

Mutations in PROM1 cause a broad spectrum of hereditary retinal diseases, from early-onset Stargardt disease to late-onset CRD, with variant effects dependent on mutation type and inheritance pattern. Novel Chinese CRD cases report compound heterozygous frameshift mutations (c.1645-1648del, c.2321delC), expanding the known mechanisms to include autophagy dysregulation. PROM1 mutations also affect renal tubule morphology, causing conditions such as Fanconi syndrome. In oncology, CD133 is a prognostic marker and therapeutic target: in colorectal cancer, CD133 expression predicts liver metastasis and 5-year survival, while in glioblastoma, patients with >10% CD133-positive cells show reduced survival and increased radioresistance. Circulating tumor cells expressing CD133 in metastatic breast cancer correlate with decreased chemotherapy response and shorter progression-free survival.

Figure 2. Potential mechanism of CD133 in cancer stem cells, illustrating signaling pathways including TRAIL/FADD-mediated apoptosis, PI3K/Akt, ERK, JNK, and Wnt pathways. (Devis-Jauregui L, et al., 2019)

In regenerative medicine, CD133 is a marker for various adult stem cells (neural, hematopoietic, intestinal). Its expression reflects stem cell functional status, influencing iPSC reprogramming efficiency and supporting neuroregeneration, as shown by AAV-mediated CD133 gene therapy in Parkinson’s models.

Targeted Interventions and Challenges

Therapeutically, CD133-targeted antibodies and ADCs have shown promise. Bispecific antibodies (CD133xCD3) recruit T cells to eliminate tumor stem cells, while ADCs combining anti-CD133 with cytotoxic agents reduce tumor burden and metastasis. CAR-T strategies targeting CD133 have shown partial responses in glioma, though normal stem cell depletion remains a concern. Gene therapy approaches for retinal disease include AAV-mediated PROM1 gene supplementation, read-through drugs for nonsense mutations, and CRISPR/Cas9-mediated in situ correction, with autophagy modulation providing additional therapeutic avenues.

Challenges remain in achieving tissue-specific targeting. PROM1’s physiological expression in renal and biliary epithelia necessitates precise delivery strategies, such as promoter-specific AAV vectors or cholesterol-modified nanocarriers. Resistance mechanisms, such as reactivation of Wnt/β-catenin signaling in CD133-negative tumor cells, suggest that combination therapies may be necessary to sustain treatment efficacy.

CD133 serves as a molecular nexus linking membrane topology and cell fate. Advances in structural biology and AI-based modeling of dynamic conformations may enable precise, context-specific therapeutic interventions, benefiting patients with hereditary retinal diseases and malignancies

Reference

Bahn MS, Ko YG. PROM1-mediated cell signal transduction in cancer stem cells and hepatocytes. BMB Rep. 2023 Feb;56(2):65-70.
Devis-Jauregui L, Eritja N, Davis ML, et al. Barzegar Behrooz A, Syahir A, Ahmad S. CD133: beyond a cancer stem cell biomarker. J Drug Target. 2019 Mar;27(3):257-269.

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