PKA-cat (cAMP-dependent), HXK2, PKA-reg (cAMP-dependent), ATP, CREB1, ODF1, CREM (repressors), FSHR, Adenylate cyclase, TSSK2, Tnp1, ATP = diphosphate + adenosine 3',5'-cyclic phosphate, cAMP, HILS1, CREM (activators), LDHC, FSH-beta, G-protein alpha-s, ACE1, KIF17, CBP, ACT
Crem signaling in testis
cAMP responsive element modulator ( CREM ) is a member of the basic domain-leucine zipper class of transcription factors which bind as homo- and heterodimers to a regulatory palindromic DNA sequence, the cAMP response element (CRE). CRE is localized in the promoter regions of cAMP responsive genes. CREM -encoding gene features multiple sites of alternative splicing. Some splice variants function as activators, e.g., CREM tau ( CREM-activators ) and some as repressors, e.g., ICER ( CREM-repressors ) of transcription. CREM is absolutely required for male fertility. The absence of CREM -dependent transcription in post-meiotic germ cells results in an arrest of spermatid differentiation and apoptosis , , .
CREM is highly expressed in testis cells. Its mRNA level is predominantly regulated by the follicle-stimulating hormone ( FSH ). The most important signaling pathway, affecting CREM activity and expression, is Adenylate cyclase/ 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 regulated by another cAMP responsive element binding protein 1 ( CREB1 ); CREM expression is alternatively regulated by autoregulatory pathway , .
In contrast to somatic cells, CREM does not appear to be phosphorylated in haploid male germ cells, and its activation is not dependent on phosphorylation or interaction with its coactivator, CREB binding protein ( CBP ). CREM activity is regulated through interactions with a germ cell-specific transcriptional co-activator Four and a half LIM domains 5 ( ACT ). The ability of ACT to regulate CREM activity is controlled by a germ cell-specific kinesin, Kinesin family member 17 ( KIF17 ), which regulates subcellular localization of ACT. KIF17 colocalizes with ACT in haploid spermatids and mediates the transport of ACT from the nucleus to the cytoplasm at specific stages of spermatid maturation. KIF17 movement is modulated by phosphorylation by PKA (c-AMP-dependent). The ability of KIF17 to shuttle between the nuclear and the cytoplasmic compartments and to transport ACT are dependent on neither its motor domain nor on microtubules , .
CREM activators are critical factors in regulation of transcriptional activity in the spermiogenic program. They are responsible for transcription of many key genes in postmeiotic 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-specific 1 ( HILS1 ), Transition protein 1 ( Tnp1 ), Hexokinase 2 ( HXK2 ), Testis-specific serine kinase 2 ( TSSK2 ). During spermatogenesis CREM repressors inhibit transcription of many genes such as FSHR , , , .