FAM162A

Human growth and transformation-dependent protein (HGTD-P), also called E2-induced gene 5 protein (E2IG5), is a protein that in humans is encoded by the FAM162A gene on chromosome 3.[4][5] This protein promotes intrinsic apoptosis in response to hypoxia via interactions with hypoxia-inducible factor-1α (HIF-1α).[4][6][7][8][9][10] As a result, it has been associated with cerebral ischemia, myocardial infarction, and various cancers.[7][11][12]

FAM162A
Identifiers
AliasesFAM162A, C3orf28, E2IG5, HGTD-P, family with sequence similarity 162 member A
External IDsOMIM: 608017 MGI: 1917436 HomoloGene: 8656 GeneCards: FAM162A
Gene location (Human)
Chr.Chromosome 3 (human)[1]
Band3q21.1Start122,384,176 bp[1]
End122,412,334 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

26355

70186

Ensembl

ENSG00000114023

ENSMUSG00000003955

UniProt

Q96A26

Q9D6U8

RefSeq (mRNA)

NM_014367

NM_027342

RefSeq (protein)

NP_055182

NP_081618

Location (UCSC)Chr 3: 122.38 – 122.41 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

HGTD-P contains two transmembrane domains that are required for its localization to the mitochondria and induction of cell death.[7]

Function

HGTD-P localizes to the mitochondria, where it participates in regulation of apoptosis.[4][7] This localization is aided by the chaperone Hsp90, which is required to stabilize the protein during the transit.[6][9] HGTD-P primarily acts in response to hypoxia by interacting with HIF-1α, which then triggers apoptotic cascades that result in the release of cytochrome C, induction of mitochondrial permeability transition, and activation of caspase-9 and 3.[4][6][7][9][10] In neuronal cells, it additionally stimulates mitochondrial release of AIFM1, which then translocates to the nucleus to effect apoptosis, which indicates that it may participate in the caspase-independent apoptotic pathway depending on cell type or organism.[4][8][9]

Clinical significance

Human growth and transformation-dependent protein (HGTD-P) is involved in intrinsic apoptosis. Apoptosis, an ancient Greek word used to describe the "falling off" of petals from flowers or leaves from trees, is a highly regulated, evolutionarily conserved, and energy-requiring process by which activation of specific signaling cascades ultimately leads to cell death. An apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[13] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. During apoptosis the cell decrease in size, loose contact with neighboring cells, and loose specialized surface elements such as microvilli and cell-cell junctions. A shift of fluid out of the cells causes cytoplasm condensation, which is followed by convolution of the nuclear and cellular outlines. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.

Due to its involvement in hypoxia, HGTD-P has been implicated in cerebral ischemia and myocardial infarction, as well as numerous cancers, including cervical cancer and gastric cancer.[7][11][12] In the case of cervical cancer, HGTD-P is expressed in the early developmental stages and, thus, may prove useful as a diagnostic marker to control the spread of the cancer. Despite its proapoptotic function, HGTD-P has been observed to coordinate with HIF-1α to promote cell growth and proliferation under hypoxic conditions in cervical cancer.[11] In the case of hypoxia-ischemia brain damage, the microRNA agomir, miR-139-5p, attenuates HGTD-P expression and brain damage, and has the therapeutic potential to treat hypoxia-ischemia brain damage.[10][14]

Interactions

HGTD-P has been shown to interact with Hsp90[6] and VDAC.[7] HIF-1α is also known to bind to the hypoxia-responsive element of the HGTD-P gene promoter and induce its transcription.[8]

References
  1. GRCh38: Ensembl release 89: ENSG00000114023 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "FAM162A - Protein FAM162A - Homo sapiens (Human)". Uniprot.org. 2006-10-31. Retrieved 2015-05-30.
  5. "FAM162A family with sequence similarity 162, member A [Homo sapiens (human)] - Gene - NCBI". Ncbi.nlm.nih.gov. Retrieved 2015-05-30.
  6. Kim JY, Kim SM, Ko JH, Yim JH, Park JH, Park JH (May 2006). "Interaction of pro-apoptotic protein HGTD-P with heat shock protein 90 is required for induction of mitochondrial apoptotic cascades". FEBS Letters. 580 (13): 3270–5. doi:10.1016/j.febslet.2006.05.001. PMID 16698020. S2CID 13992300.
  7. Lee MJ, Kim JY, Suk K, Park JH (May 2004). "Identification of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway". Molecular and Cellular Biology. 24 (9): 3918–27. doi:10.1128/mcb.24.9.3918-3927.2004. PMC 387743. PMID 15082785.
  8. Qu Y, Mao M, Zhao F, Zhang L, Mu D (Aug 2009). "Proapoptotic role of human growth and transformation-dependent protein in the developing rat brain after hypoxia-ischemia". Stroke: A Journal of Cerebral Circulation. 40 (8): 2843–8. doi:10.1161/STROKEAHA.109.553644. PMID 19520982.
  9. Cho YE, Ko JH, Kim YJ, Yim JH, Kim SM, Park JH (Apr 2007). "mHGTD-P mediates hypoxic neuronal cell death via the release of apoptosis-inducing factor". Neuroscience Letters. 416 (2): 144–9. doi:10.1016/j.neulet.2007.01.073. PMID 17316997. S2CID 33662614.
  10. Webster KA, Graham RM, Thompson JW, Spiga MG, Frazier DP, Wilson A, Bishopric NH (2006). "Redox stress and the contributions of BH3-only proteins to infarction". Antioxidants & Redox Signaling. 8 (9–10): 1667–76. doi:10.1089/ars.2006.8.1667. PMID 16987020.
  11. Cho YE, Kim JY, Kim YJ, Kim YW, Lee S, Park JH (Sep 2010). "Expression and clinicopathological significance of human growth and transformation-dependent protein (HGTD-P) in uterine cervical cancer". Histopathology. 57 (3): 479–82. doi:10.1111/j.1365-2559.2010.03627.x. PMC 3066410. PMID 20840676.
  12. Cho YE, Kim JY, Kim YW, Park JH, Lee S (Jul 2009). "Expression and prognostic significance of human growth and transformation-dependent protein in gastric carcinoma and gastric adenoma". Human Pathology. 40 (7): 975–81. doi:10.1016/j.humpath.2008.12.007. PMID 19269009.
  13. Kerr JF, Wyllie AH, Currie AR (Aug 1972). "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer. 26 (4): 239–57. doi:10.1038/bjc.1972.33. PMC 2008650. PMID 4561027.
  14. Qu Y, Wu J, Chen D, Zhao F, Liu J, Yang C, Wei D, Ferriero DM, Mu D (Mar 2014). "MiR-139-5p inhibits HGTD-P and regulates neuronal apoptosis induced by hypoxia-ischemia in neonatal rats". Neurobiology of Disease. 63: 184–93. doi:10.1016/j.nbd.2013.11.023. PMID 24333693. S2CID 26305530.
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