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Transcription CREM signaling in testis

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Transcription CREM signaling in testis

Crem signaling in testis

cAMP responsive element modulator ( CREM ) is a member of the basicdomain-leucine zipper class of transcription factors which bind as homo- and heterodimersto a regulatory palindromic DNA sequence, the cAMP response element (CRE). CRE islocalized in the promoter regions of cAMP responsive genes. CREM -encoding genefeatures multiple sites of alternative splicing. Some splice variants function asactivators, e.g., CREM tau ( CREM-activators ) and some as repressors, e.g., ICER( CREM-repressors ) of transcription. CREM is absolutely required for malefertility. The absence of CREM -dependent transcription in post-meiotic germ cellsresults in an arrest of spermatid differentiation and apoptosis [1], [2], [3].

CREM is highly expressed in testis cells. Its mRNA level is predominantlyregulated by the follicle-stimulating hormone ( FSH ). The most importantsignaling pathway, affecting CREM activity and expression, is Adenylatecyclase/ cAMP/ Protein kinase A, cAMP-dependent ( PKA(c-AMP-dependent) ) -dependent pathway that is activated by G-protein alpha-s-coupled receptors, such as Follicle stimulating hormone receptor ( FSHR ).CREM gene consists of CRE regions in the promoters and its expression is regulatedby another cAMP responsive element binding protein 1 ( CREB1 ); CREMexpression is alternatively regulated by autoregulatory pathway [4], [3].

In contrast to somatic cells, CREM does not appear to be phosphorylated inhaploid male germ cells, and its activation is not dependent on phosphorylation orinteraction with its coactivator, CREB binding protein ( CBP ). CREMactivity is regulated through interactions with a germ cell-specific transcriptionalco-activator Four and a half LIM domains 5 ( ACT ). The ability of ACT toregulate CREM activity is controlled by a germ cell-specific kinesin, Kinesinfamily member 17 ( KIF17 ), which regulates subcellular localization of ACT. KIF17 colocalizes with ACT in haploid spermatids and mediates thetransport of ACT from the nucleus to the cytoplasm at specific stages of spermatidmaturation. KIF17 movement is modulated by phosphorylation by PKA(c-AMP-dependent). The ability of KIF17 to shuttle between the nuclear andthe cytoplasmic compartments and to transport ACT are dependent on neither itsmotor domain nor on microtubules [5], [3].

CREM repressors (e.g., ICER) activity is primarily determined by theirintracellular concentration [6], [7], [3].

CREM activators are critical factors in regulation of transcriptional activityin the spermiogenic program. They are responsible for transcription of many key genes inpostmeiotic germ cells, such as Outer dense fiber of sperm tails 1 ( ODF1 ),Lactate dehydrogenase C ( LDHC ), Angiotensin I converting enzyme(peptidyl-dipeptidase A) 1 ( ACE1 ), Histone linker H1 domain, spermatid-specific1 ( HILS1 ), Transition protein 1 ( Tnp1 ), Hexokinase 2 ( HXK2 ),Testis-specific serine kinase 2 ( TSSK2 ). During spermatogenesis CREMrepressors inhibit transcription of many genes such as FSHR [4],[8], [1], [9].