CKLF-like MARVEL transmembrane domain-containing 5

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CKLF-like MARVEL transmembrane domain-containing 5 (CMTM5), previously termed chemokine-like factor superfamily 5 (i.e. CKLFSF5), designates any one of the six protein isoforms (termed CMTM5-v1 to CMTM5-v6) encoded by six different alternative splices of its gene, CMTM5; CMTM5-v1 is the most studied of these isoforms. [1] The CMTM5 gene is located in band 11.2 on the long (i.e. "q") arm of chromosome 14. [2]

Contents

The CMTM5 isoforms are members of the CKLF-like MARVEL transmembrane domain-containing family (CMTM). This family consists of 9 proteins although most of them are known to have one or more isoforms. These proteins are: chemokine-like factor (i.e. CLF, the founding member of the family) and CEF-like marvel transmembrane domain-containing 1 through 8 (i.e. CMTM1 through CMTM8). [3] All of these proteins as well as the genes responsible for their production (i.e. CKLF and CMTM1 to CMTM8, respectively) have similar structures [3] but vary in their apparent physiological and pathological functions. [2] [4] [5] [6] Preliminary studies suggest that CMTM5-v1 (which cells commonly secrete to the extracellular spaces such as the blood [7] ) or an unspecified CMTM5 isoform has various functions including involvements in regulating the autoimmune system, the development of numerous types of cancers, and the cardiovascular system.

Autoimmune system

The methylation of certain CpG clusters (i.e. DNA areas high in cytosine and guanine) regulate the transcriptional activity of nearby genes. That is, the methylation of a cluster(s) regulates its nearby gene by blocking it from making mRNAs and thereby the proteins encoded by these mRNAs. Studies find that the CMTM5 gene in the DNA isolated from the blood of individuals with the autoimmune diseases of systemic lupus erythematosus and primary Sjögren's syndrome (i.e. Sjorgen's syndrome not associated with other health problems or connective tissue diseases) is hyper-methylated at its CpG cluster(s) and thereby less active or inactive. On the other hand, the CpG cluster(s) controlling the CMTM5 gene in the blood of individuals with the autoimmune disease of rheumatoid arthritis are hypo-methylated and therefore highly active. These methylation changes, the studies suggest, regulate the function of immunologically active blood cells [5] (and, perhaps, blood platelets [8] ) and thereby the development, maintenance, and/or worsening of the cited autoimmune diseases. [2] [5] [8] Further studies are required to prove that these methylations contribute to the immunologic dysregulations occurring in these (and perhaps other) autoimmune diseases and can serve as clinical markers of disease severity and/or as therapeutic targets for controlling the diseases. [2]

Cancers

Studies have reported that: 1) the levels of CMTM5-v1 in the malignant tissues of patients with prostate cancer are lower than the levels in their nearby normal prostate gland tissues [9] as well as in the tissues of patients with benign prostate hyperplasia; [10] 2) patients with lower prostate cancer tissue levels of CMTM5-v1 have higher prostate cancer Gleason scores and therefore poorer prognoses than patients with higher prostate cancer tissue levels of CMTM5-v1; [9] and 3) the forced overexpression of CMTM5-v1 in cultured DU145 cells (a human prostate cancer cell line) reduces, while the forced higher expression of the CMTM5-v1 levels increases, their proliferation and migration. [4] [9] [10] Similar findings for an unspecified CMTM5 isoform are reported in ovarian cancer, [4] [11] hepatocellular carcinoma, [4] [12] pancreatic cancer, [4] [13] non-small-cell lung carcinoma, [4] [14] renal cell carcinoma, [4] [15] and breast cancer. [16] The forced over expression of CMTM5-v1 in Huh7 human hepatic cells also inhibited the ability of these cells to grow in a mouse model of cancer. [12] Finally, various cancer human cell lines including those of the liver, breast, prostate, colon, stomach, nasopharynx, laryngopharynx, esophagus, lung, and cervix express low levels of, or no, CMTM5-v1 and concurrently have highly methylated CpG sites near to the CMTM5 gene. [17] These findings suggest that the CMTM5 gene may act as a tumor suppressor gene, i.e. a normal gene whose product(s) inhibit the development and/or progression of various cancers. The findings also support further studies to confirm and expand these relationships and determine if the expression of CMTM5 isoforms can be used as tumor markers for these cancers severities/prognoses and/or targets as for treating them. [4]

Cardiovascular system

A case–control study of hospitalized patients found that the blood plasma levels of CMTM5 protein and CMTM5 messenger RNA (i.e. mRNA) in 350 patients with coronary artery disease were significantly higher than a matched group of 350 patients without this disease. [18] The same research group similarly studied 124 hospitalized patients who had in place a coronary artery stent. They found that high blood plasma levels of CMTM5 mRNA were associated with a higher rate of subsequently developing stenosis (i.e. narrowing) in their stents than patients with lower levels of this mRNA. [19] Furthermore, the forced overexpression of the CMTM5 gene inhibited the proliferation and migration of cultured human endothelial cells, [19] [20] while the forced suppression of the CMTM5 gene promote the proliferation of these cells. [20] These studies suggest that the CMTM5 gene, one of its mRNAs, and/or one of its CMTM5 proteins may promote atherosclerosis-based coronary artery disease and the stenosis of coronary artery stents and do so by inhibiting vascular endothelial cells from functioning to inhibit atherosclerosis and stent occlusion. More studies are necessary to confirm and further define these relationships; to determine if expression of the CMTM5 gene's or its products can be used as makers for patient susceptibilities to coronary artery/stent occlusions; and to determine if this gene or its products can used clinically as targets for preventing or decreasing the frequency of these occlusions. [19] [20]

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The CKLF-like MARVEL transmembrane domain-containing family (CMTM), previously termed the chemokine-like factor superfamily (CKLFSF), consists of 9 proteins, some of which have various isoforms due to alternative splicing of their respective genes. These proteins along with their isoforms are:

CKLF like MARVEL transmembrane domain-containing 8, previously termed chemokine-like factor superfamily 8 has at least two isoforms, the CMTM8 and CMTM8-v2 proteins. Protein isoforms are variant products that are made by the alternative splicing of a single gene. The gene for these isoforms, CMTM8, is located in band 22 on the short arm of chromosome 3. The CMTM8 gene and its CMTM8 and CMTM8-v2 proteins belong to the CKLF-like MARVEL transmembrane domain-containing family of structurally and functionally related genes and proteins. The CMTM8 protein is the full-length and predominant product of the CMTM8 gene. This protein is expressed in a wide range of normal adult and fetal tissues while relatively little is known about the CMTM8-v2 protein. Studies suggest that the CMTM8 protein may be involved in the development of various cancers.

CKLF like MARVEL transmembrane domain-containing 1, formerly termed chemokine-like factor superfamily 1, has 23 known isoforms, the CMTM1-v1 to CMTM1-v23 proteins. Protein isoforms are variant products that are made by alternative splicing of a single gene. The gene for these isoforms, CMTM1, is located in band 22 on the long arm of chromosome 16. The CMTM1 gene and its 23 isoforms belong to the CKLF-like MARVEL transmembrane domain-containing family of structurally and functionally related genes and proteins. CMTM1 proteins are weakly express in a wide range of normal tissues but are far more highly expressed in normal testes as well as the malignant cells of certain types of cancer.

CKLF like MARVEL transmembrane domain-containing 4, formerly termed chemokine-like factor superfamily 4, is a small transmembrane protein which passes the plasma membrane four times. It has 3 known isoforms, the CMTM4-v1 to CMTM4-v3 proteins. Protein isoforms are variant products that are made by alternative splicing of a single gene. The gene for the CMTM4 isoforms is located in band 22 on the long arm of chromosome 16. The CMTM4 gene and its 3 isoform proteins belong to the CKLF-like MARVEL transmembrane domain-containing family of structurally and functionally related genes and proteins. CMTM4-v1 and CMTM4-v2 are widely expressed in multiple human tissue while CMTM4-v3 has been detected only in the kidney and placental tissues.

References

  1. ↑ Li M, Luo F, Tian X, Yin S, Zhou L, Zheng S (2020). "Chemokine-Like Factor-Like MARVEL Transmembrane Domain-Containing Family in Hepatocellular Carcinoma: Latest Advances". Frontiers in Oncology. 10: 595973. doi: 10.3389/fonc.2020.595973 . PMC   7691587 . PMID   33282744.
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  3. 1 2 Han W, Ding P, Xu M, Wang L, Rui M, Shi S, Liu Y, Zheng Y, Chen Y, Yang T, Ma D (June 2003). "Identification of eight genes encoding chemokine-like factor superfamily members 1-8 (CKLFSF1-8) by in silico cloning and experimental validation". Genomics. 81 (6): 609–17. doi:10.1016/s0888-7543(03)00095-8. PMID   12782130.
  4. 1 2 3 4 5 6 7 8 Wu J, Li L, Wu S, Xu B (August 2020). "CMTM family proteins 1-8: roles in cancer biological processes and potential clinical value". Cancer Biology & Medicine. 17 (3): 528–542. doi:10.20892/j.issn.2095-3941.2020.0032. PMC   7476098 . PMID   32944388.
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  7. ↑ Li H, Guo X, Shao L, Plate M, Mo X, Wang Y, Han W (March 2010). "CMTM5-v1, a four-transmembrane protein, presents a secreted form released via a vesicle-mediated secretory pathway". BMB Reports. 43 (3): 182–7. doi: 10.5483/bmbrep.2010.43.3.182 . PMID   20356458. S2CID   32280803.
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  11. ↑ Li P, Liu K, Li L, Yang M, Gao W, Feng J, Lv Y, Qu X, Kong B (October 2011). "Reduced CMTM5 expression correlates with carcinogenesis in human epithelial ovarian cancer". International Journal of Gynecological Cancer. 21 (7): 1248–55. doi:10.1097/IGC.0b013e3182259c31. PMID   21841490. S2CID   23134052.
  12. 1 2 Xu G, Dang C (2017). "CMTM5 is downregulated and suppresses tumour growth in hepatocellular carcinoma through regulating PI3K-AKT signalling". Cancer Cell International. 17: 113. doi: 10.1186/s12935-017-0485-8 . PMC   5707824 . PMID   29213215.
  13. ↑ Guo X, Li T, Wang Y, Shao L, Zhang Y, Ma D, Han W (September 2009). "CMTM5 induces apoptosis of pancreatic cancer cells and has synergistic effects with TNF-alpha". Biochemical and Biophysical Research Communications. 387 (1): 139–42. doi:10.1016/j.bbrc.2009.06.148. PMID   19577543.
  14. ↑ Wu K, Li X, Gu H, Yang Q, Liu Y, Wang L (2019). "Research Advances in CKLF-like MARVEL Transmembrane Domain-containing Family in Non-small Cell Lung Cancer". International Journal of Biological Sciences. 15 (12): 2576–2583. doi:10.7150/ijbs.33733. PMC   6854381 . PMID   31754330.
  15. ↑ Cai B, Xiao Y, Li Y, Zheng S (August 2017). "CMTM5 inhibits renal cancer cell growth through inducing cell-cycle arrest and apoptosis". Oncology Letters. 14 (2): 1536–1542. doi:10.3892/ol.2017.6350. PMC   5529942 . PMID   28789377.
  16. ↑ Chen Z, Cui N, Zhao JS, Wu JF, Ma F, Li C, Liu XY (January 2021). "Expressions of ZNF436, β-catenin, EGFR, and CMTM5 in breast cancer and their clinical significances". European Journal of Histochemistry. 65 (1). doi:10.4081/ejh.2021.3173. PMC   7856825 . PMID   33478201.
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