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PMID: 25344376 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Expression, function, and regulation of the testis-enriched heat shock HSPA2 gene in rodents and humans.

Cell stress & chaperones ·Vol. 20 ·No. 2 ·2015-03-00 ·Pages 221-35

Scieglinska D, Krawczyk Z

Abstract

The HSPA2 gene is a poorly characterized member of the HSPA (HSP70) family. HSPA2 was originally described as testis-specific and expressed at the highest level in pachytene spermatocytes of rodents, the expression of which is not induced by heat shock. HSPA2 is crucial for male fertility. However, recent advances have shown that HSPA2 is expressed in various tumors and in certain types of somatic tissues. In this review, we summarize the current knowledge on the HSPA2 expression pattern, including information on transcriptional, translational, posttranslational, and epigenetic mechanisms which regulate HSPA2 expression. We also present and discuss the current views concerning the functions of the HSPA2 protein in spermatogenetic, somatic, and cancer cells. The knowledge of the properties of HSPA2, although limited, shows this protein as a unique member of the HSPA family. However, understanding whether this protein could become a relevant cancer biomarker or a therapeutically applicable target requires extensive further studies.

MeSH Terms
Animals Gene Expression HSP70 Heat-Shock Proteins/chemistry,genetics,metabolism Hippocampus/metabolism Humans Male Neoplasms/metabolism,pathology Regulatory Elements, Transcriptional/genetics Spermatogenesis Testis/metabolism
Chemicals
HSP70 Heat-Shock Proteins HSPA2 protein, human
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Scieglinska Dorota
Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej 15, 44-101, Gliwice, Poland, [email protected].
Krawczyk Zdzislaw
References (101)
101 references, click to expand
  1. HSPA2 overexpression protects V79 fibroblasts against bortezomib-induced apoptosis.
    Biochem Cell Biol. 2012 Apr;90(2):224-31 PMID: 22397456
  2. Identification of the gene for the developmentally expressed 70 kDa heat-shock protein (P70) of mouse spermatogenic cells.
    Dev Biol. 1992 Mar;150(1):1-11 PMID: 1537426
  3. HIF-1alpha controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1).
    Biochim Biophys Acta. 2008 Feb;1783(2):323-33 PMID: 18166158
  4. Effect of age and busulphan treatment on the hsp70 gene-related transcript level in rat testes.
    Int J Androl. 1989 Feb;12(1):72-9 PMID: 2469655
  5. Spermiogenesis is impaired in mice bearing a targeted mutation in the protein phosphatase 1cgamma gene.
    Dev Biol. 1999 Jan 1;205(1):98-110 PMID: 9882500
  6. Expression of HSPA2 in human hepatocellular carcinoma and its clinical significance.
    Tumour Biol. 2014 Nov;35(11):11283-7 PMID: 25117073
  7. Mutation of Eif4g3, encoding a eukaryotic translation initiation factor, causes male infertility and meiotic arrest of mouse spermatocytes.
    Development. 2010 May;137(10):1699-707 PMID: 20430745
  8. Stress-induced localization of HSPA6 (HSP70B') and HSPA1A (HSP70-1) proteins to centrioles in human neuronal cells.
    Cell Stress Chaperones. 2014 May;19(3):321-7 PMID: 24061851
  9. Developmental expression of heat shock proteins 60, 70, 90, and A2 in rabbit testis.
    Cell Tissue Res. 2011 May;344(2):355-63 PMID: 21538228
  10. Expression of hsp70-related gene in developing and degenerating rat testis.
    Mol Biol Rep. 1987;12(1):35-41 PMID: 2442598
  11. Evaluation of HSPA2 in fertile and infertile individuals.
    Andrologia. 2013 Feb;45(1):66-72 PMID: 22670834
  12. Heat shock proteins on the human sperm surface.
    J Reprod Immunol. 2010 Jan;84(1):32-40 PMID: 19962198
  13. FISH assessment of aneuploidy frequencies in mature and immature human spermatozoa classified by the absence or presence of cytoplasmic retention.
    Hum Reprod. 2001 Jun;16(6):1209-17 PMID: 11387294
  14. Cloning, sequencing, and mapping of the human chromosome 14 heat shock protein gene (HSPA2).
    Genomics. 1994 Sep 1;23(1):85-93 PMID: 7829106
  15. Structure of the 5' region of the Hst70 gene transcription unit: presence of an intron and multiple transcription initiation sites.
    Biochem J. 2001 Oct 1;359(Pt 1):129-37 PMID: 11563976
  16. From meiosis to postmeiotic events: the secrets of histone disappearance.
    FEBS J. 2010 Feb;277(3):599-604 PMID: 20015078
  17. Sperm plasma membrane remodeling during spermiogenetic maturation in men: relationship among plasma membrane beta 1,4-galactosyltransferase, cytoplasmic creatine phosphokinase, and creatine phosphokinase isoform ratios.
    Biol Reprod. 1997 Apr;56(4):1020-4 PMID: 9096886
  18. Loss of protein phosphatase 1c{gamma} (PPP1CC) leads to impaired spermatogenesis associated with defects in chromatin condensation and acrosome development: an ultrastructural analysis.
    Reproduction. 2010 Jun;139(6):1021-9 PMID: 20385779
  19. Hsp70 accelerates the recovery of nucleolar morphology after heat shock.
    EMBO J. 1984 Dec 20;3(13):3095-100 PMID: 6441707
  20. Cloning of a hsp70-related gene expressed in mouse spermatids.
    Biochem Biophys Res Commun. 1990 Jan 15;166(1):43-9 PMID: 2302214
  21. Differential expression of HSPA1 and HSPA2 proteins in human tissues; tissue microarray-based immunohistochemical study.
    Histochem Cell Biol. 2011 Apr;135(4):337-50 PMID: 21373891
  22. The expression pattern of the 70-kDa heat shock protein Hspa2 in mouse tissues.
    Histochem Cell Biol. 2009 Sep;132(3):319-30 PMID: 19462178
  23. New candidate targets of protein phosphatase-1c-gamma-2 in mouse testis revealed by a differential phosphoproteome analysis.
    Int J Androl. 2011 Aug;34(4):339-51 PMID: 20618881
  24. Vertebrate nucleoplasmin and NASP: egg histone storage proteins with multiple chaperone activities.
    FASEB J. 2012 Dec;26(12):4788-804 PMID: 22968912
  25. Spermatocyte-specific expression of constitutively active heat shock factor 1 induces HSP70i-resistant apoptosis in male germ cells.
    Cell Death Differ. 2006 Feb;13(2):212-22 PMID: 16151457
  26. Poly(ADP-ribose) polymerase-2 contributes to the fidelity of male meiosis I and spermiogenesis.
    Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14854-9 PMID: 17001008
  27. Promoter of the heat shock testis-specific Hsp70.2/Hst70 gene is active in nervous system during embryonic development of mice.
    Anat Embryol (Berl). 2006 Nov;211(6):631-8 PMID: 17047988
  28. Decreased expression of the heat shock protein hsp70-2 is associated with the pathogenesis of male infertility.
    Fertil Steril. 2001 Dec;76(6):1136-9 PMID: 11730740
  29. Post-meiotic shifts in HSPA2/HSP70.2 chaperone activity during mouse spermatogenesis.
    J Biol Chem. 2006 Dec 8;281(49):37888-92 PMID: 17035236
  30. Bat3 deficiency accelerates the degradation of Hsp70-2/HspA2 during spermatogenesis.
    J Cell Biol. 2008 Aug 11;182(3):449-58 PMID: 18678708
  31. Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples.
    Clin Cancer Res. 2010 Dec 1;16(23):5842-51 PMID: 20975101
  32. Changes in the expression profile of the meiosis-involved mismatch repair genes in impaired human spermatogenesis.
    J Androl. 2010 Jul-Aug;31(4):346-57 PMID: 20075417
  33. Transcriptional upregulation of HSP70-2 by HIF-1 in cancer cells in response to hypoxia.
    Int J Cancer. 2009 Jan 15;124(2):298-305 PMID: 18844219
  34. HSP70-2 is part of the synaptonemal complex in mouse and hamster spermatocytes.
    Chromosoma. 1996 Mar;104(6):414-21 PMID: 8601336
  35. Isolation and nucleotide sequence analysis of the rat testis-specific major heat-shock protein (HSP70)-related gene.
    Biochim Biophys Acta. 1990 Jan 30;1048(1):93-9 PMID: 1688714
  36. Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer.
    Cancer Res. 2007 Mar 15;67(6):2559-67 PMID: 17363574
  37. Location of promoter elements necessary and sufficient to direct testis-specific expression of the Hst70/Hsp70.2 gene.
    Biochem J. 2004 May 1;379(Pt 3):739-47 PMID: 14766014
  38. Disruption of poly(ADP-ribose) homeostasis affects spermiogenesis and sperm chromatin integrity in mice.
    Biol Reprod. 2009 Jul;81(1):46-55 PMID: 19264700
  39. Developmentally regulated expression of Hsp70-2 and a Hsp70-2/lacZ transgene during spermatogenesis.
    Dev Biol. 1996 Mar 15;174(2):310-21 PMID: 8631503
  40. HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis.
    Mol Biol Cell. 2014 Aug 1;25(15):2260-71 PMID: 24899640
  41. A hsp70-related gene is constitutively highly expressed in testis of rat and mouse.
    Mol Biol Rep. 1987;12(1):27-34 PMID: 2442597
  42. HSPA2 is expressed in human tumors and correlates with clinical features in non-small cell lung carcinoma patients.
    Anticancer Res. 2014 Jun;34(6):2833-40 PMID: 24922646
  43. The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities.
    Biochem J. 2011 Apr 1;435(1):127-42 PMID: 21231916
  44. Developmental-stage-specific expression of the hsp70 gene family during differentiation of the mammalian male germ line.
    Mol Cell Biol. 1987 May;7(5):1791-6 PMID: 3600644
  45. BAG6/BAT3: emerging roles in quality control for nascent polypeptides.
    J Biochem. 2013 Feb;153(2):147-60 PMID: 23275523
  46. Germ cell-specific heat shock protein 70-2 is expressed in cervical carcinoma and is involved in the growth, migration, and invasion of cervical cells.
    Cancer. 2010 Aug 15;116(16):3785-96 PMID: 20564126
  47. The ERE-like sequence from the promoter region of the testis specific hsp70-related gene is not estrogen responsive.
    Cell Biol Int Rep. 1992 Sep;16(9):937-48 PMID: 1423660
  48. Guidelines for the nomenclature of the human heat shock proteins.
    Cell Stress Chaperones. 2009 Jan;14(1):105-11 PMID: 18663603
  49. Methylated DNA collected by tampons--a new tool to detect endometrial cancer.
    Cancer Epidemiol Biomarkers Prev. 2004 May;13(5):882-8 PMID: 15159323
  50. Oxygen levels in normal and previously irradiated human skin as assessed by EF5 binding.
    J Invest Dermatol. 2006 Dec;126(12):2596-606 PMID: 16810299
  51. Functional analysis of spermatocyte-specific hst70 gene promoter in transgenic mice.
    Acta Biochim Pol. 1994;41(2):103-5 PMID: 7976013
  52. The molecular chaperone HSPA2 plays a key role in regulating the expression of sperm surface receptors that mediate sperm-egg recognition.
    PLoS One. 2012;7(11):e50851 PMID: 23209833
  53. The structural and functional analysis of the human HSPA2 gene promoter region.
    Acta Biochim Pol. 2007;54(1):99-106 PMID: 17369882
  54. The stem cell signature of CHH/CHG methylation is not present in 271 cancer associated 5'UTR gene regions.
    Biochimie. 2012 Nov;94(11):2345-52 PMID: 22750649
  55. Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update.
    Arch Toxicol. 2013 Jan;87(1):19-48 PMID: 22885793
  56. Creatine kinase immunocytochemistry of human sperm-hemizona complexes: selective binding of sperm with mature creatine kinase-staining pattern.
    Fertil Steril. 1994 Jan;61(1):136-42 PMID: 8293828
  57. Sense and antisense transcripts of the developmentally regulated murine hsp70.2 gene are expressed in distinct and only partially overlapping areas in the adult brain.
    Brain Res Mol Brain Res. 1996 Apr;37(1-2):85-95 PMID: 8738139
  58. The GC-box is critical for high level expression of the testis-specific Hsp70.2/Hst70 gene.
    Acta Biochim Pol. 2007;54(1):107-12 PMID: 17311111
  59. Temporally regulated traffic of HuR and its associated ARE-containing mRNAs from the chromatoid body to polysomes during mouse spermatogenesis.
    PLoS One. 2009;4(3):e4900 PMID: 19333380
  60. Expression of a testis-specific hsp70 gene-related RNA in defined stages of rat seminiferous epithelium.
    J Cell Biol. 1988 Oct;107(4):1317-23 PMID: 3170632
  61. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology.
    Nature. 2010 Jan 28;463(7280):549-53 PMID: 20111001
  62. Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse.
    J Cell Sci. 2011 Dec 15;124(Pt 24):4172-83 PMID: 22193962
  63. Arrest of spermatogenesis in mice expressing an active heat shock transcription factor 1.
    EMBO J. 2000 Apr 3;19(7):1545-54 PMID: 10747023
  64. Expression of the testis-specific HSP70-related gene (hst70 gene) in somatic non-testicular rat tissues revealed by RT-PCR and transgenic mice analysis.
    Cell Biol Int. 1997 Dec;21(12):813-21 PMID: 9812345
  65. Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis.
    Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):114-23 PMID: 16434596
  66. Cytoplasmic extrusion and the switch from creatine kinase B to M isoform are completed by the commencement of epididymal transport in human and stallion spermatozoa.
    J Androl. 1998 Jan-Feb;19(1):11-20 PMID: 9537287
  67. Linker histones stimulate HSPA2 ATPase activity through NASP binding and inhibit CDC2/Cyclin B1 complex formation during meiosis in the mouse.
    Biol Reprod. 2009 Oct;81(4):739-48 PMID: 19553603
  68. Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells.
    Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):E3388-97 PMID: 23959860
  69. Expression of a constitutively active mutant of heat shock factor 1 under the control of testis-specific hst70 gene promoter in transgenic mice induces degeneration of seminiferous epithelium.
    Acta Biochim Pol. 2003;50(2):535-41 PMID: 12833178
  70. Investigation of the mechanisms by which the molecular chaperone HSPA2 regulates the expression of sperm surface receptors involved in human sperm-oocyte recognition.
    Mol Hum Reprod. 2013 Mar;19(3):120-35 PMID: 23247813
  71. The HspA2 protein localizes in nucleoli and centrosomes of heat shocked cancer cells.
    J Cell Biochem. 2008 Aug 15;104(6):2193-206 PMID: 18452162
  72. Parp2 is required for the differentiation of post-meiotic germ cells: identification of a spermatid-specific complex containing Parp1, Parp2, TP2 and HSPA2.
    Exp Cell Res. 2009 Oct 1;315(16):2824-34 PMID: 19607827
  73. Expression of the HSPA2 gene in ejaculated spermatozoa from adolescents with and without varicocele.
    Fertil Steril. 2006 Dec;86(6):1659-63 PMID: 17007855
  74. Distinct transcripts are recognized by sense and antisense riboprobes for a member of the murine HSP70 gene family, HSP70.2, in various reproductive tissues.
    Mol Reprod Dev. 1996 Jan;43(1):17-24 PMID: 9110944
  75. In vivo electroporation of the testis versus transgenic mice model in functional studies of spermatocyte-specific hst70 gene promoter: A comparative study.
    Mol Reprod Dev. 2003 Aug;65(4):382-8 PMID: 12840811
  76. The stress of protein misfolding: from single cells to multicellular organisms.
    Cold Spring Harb Perspect Biol. 2011 Jun 01;3(6): PMID: 21536706
  77. Heat shock transcription factor 1 down-regulates spermatocyte-specific 70 kDa heat shock protein expression prior to the induction of apoptosis in mouse testes.
    Genes Cells. 2007 Apr;12(4):487-99 PMID: 17397396
  78. Analysis of aberrant DNA methylation and human papillomavirus DNA in cervicovaginal specimens to detect invasive cervical cancer and its precursors.
    Clin Cancer Res. 2004 May 15;10(10):3396-400 PMID: 15161694
  79. Characterization and inducibility of hsp 70 proteins in the male mouse germ line.
    J Cell Biol. 1990 Nov;111(5 Pt 1):1785-92 PMID: 2229174
  80. Depletion of the histone chaperone tNASP inhibits proliferation and induces apoptosis in prostate cancer PC-3 cells.
    Reprod Biol Endocrinol. 2011 Apr 16;9:50 PMID: 21496299
  81. Overexpression of HSPA2 is correlated with poor prognosis in esophageal squamous cell carcinoma.
    World J Surg Oncol. 2013 Jun 18;11:141 PMID: 23777267
  82. Heteromeric complexes of heat shock protein 70 (HSP70) family members, including Hsp70B', in differentiated human neuronal cells.
    Cell Stress Chaperones. 2010 Sep;15(5):545-53 PMID: 20084477
  83. Hsp70 protects mitotic cells against heat-induced centrosome damage and division abnormalities.
    Mol Biol Cell. 2005 Aug;16(8):3776-85 PMID: 15930131
  84. HSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes.
    Development. 1997 Aug;124(15):3007-14 PMID: 9247342
  85. Heat shock protein 2 promoter drives Cre expression in spermatocytes of transgenic mice.
    Genesis. 2010 Feb;48(2):114-20 PMID: 20027617
  86. Transcriptional regulation and binding of heat shock factor 1 and heat shock factor 2 to 32 human heat shock genes during thermal stress and differentiation.
    Cell Stress Chaperones. 2004 Mar;9(1):21-8 PMID: 15270074
  87. Comprehensive genome methylation analysis in bladder cancer: identification and validation of novel methylated genes and application of these as urinary tumor markers.
    Clin Cancer Res. 2011 Sep 1;17(17):5582-92 PMID: 21788354
  88. Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3264-8 PMID: 8622925
  89. Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms.
    Genes Dev. 2005 Mar 1;19(5):570-82 PMID: 15741319
  90. A 252 bp upstream region of the rat spermatocyte-specific hst70 gene is sufficient to promote expression of the hst70-CAT hybrid gene in testis and brain of transgenic mice.
    Biochim Biophys Acta. 1995 Nov 7;1264(2):191-200 PMID: 7495863
  91. Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion.
    Eur J Cancer. 2010 Jan;46(1):207-15 PMID: 19914824
  92. Putative creatine kinase M-isoform in human sperm is identifiedas the 70-kilodalton heat shock protein HspA2.
    Biol Reprod. 2000 Sep;63(3):925-32 PMID: 10952940
  93. Identification and sequence analysis of a new member of the mouse HSP70 gene family and characterization of its unique cellular and developmental pattern of expression in the male germ line.
    Mol Cell Biol. 1988 Jul;8(7):2925-32 PMID: 3405224
  94. HSP70-2 is required for desynapsis of synaptonemal complexes during meiotic prophase in juvenile and adult mouse spermatocytes.
    Development. 1997 Nov;124(22):4595-603 PMID: 9409676
  95. hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions.
    BMC Evol Biol. 2008 Jan 23;8:19 PMID: 18215318
  96. Specific expression of heat shock protein HspA2 in human male germ cells.
    Mol Hum Reprod. 1999 Dec;5(12):1122-6 PMID: 10587366
  97. Oligozoospermia and heat-shock protein expression in ejaculated spermatozoa.
    Hum Reprod. 2006 Jul;21(7):1791-4 PMID: 16517558
  98. The RNA-binding protein ELAVL1/HuR is essential for mouse spermatogenesis, acting both at meiotic and postmeiotic stages.
    Mol Biol Cell. 2011 Aug 15;22(16):2875-85 PMID: 21737689
  99. Inducible 70 kDa heat shock protein does not protect spermatogenic cells from damage induced by cryptorchidism.
    Int J Androl. 2007 Apr;30(2):80-7 PMID: 17014532
  100. Sperm maturity and treatment choice of in vitro fertilization (IVF) or intracytoplasmic sperm injection: diminished sperm HspA2 chaperone levels predict IVF failure.
    Fertil Steril. 2002 May;77(5):910-8 PMID: 12009343
  101. Barcoding heat shock proteins to human diseases: looking beyond the heat shock response.
    Dis Model Mech. 2014 Apr;7(4):421-34 PMID: 24719117
Article Info
Journal
Cell stress & chaperones
Abbr.
Cell Stress Chaperones
ISSN
1466-1268
DOI
10.1007/s12192-014-0548-x
Email
[email protected]
Published
2015-03-00
Epub
2014-00-25
Pages
221-35
Language
English
Region
Netherlands
NLM ID
9610925
PMCID
PMC4326386
Subset
IM
External Links
PubMed source DOI: 10.1007/s12192-014-0548-x PMC Full Text View journal details
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