Ca2+ Channels in Anterior Pituitary Somatotrophs: A Therapeutic Perspective

Nussinovitch, Itzhak

doi:10.1210/en.2018-00743

Cited by 5 publications

(4 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Higher expression of dopamine receptors DRD1 and DRD2 was in turn found in group 3. Irrespectively to receptor activation, Ca 2+ influx through voltage-gated Ca 2+ channels (VGCCs) also plays an important role in GH secretion [ 24 ]. CACNA1C and CACNA1D encoding VGCCs were identified as expressed at significantly higher levels in groups 1 and 2 as compared to group 3 ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly

Rymuza

Kober

Rusetska

et al. 2022

Cells

View full text Add to dashboard Cite

Acromegaly results from growth hormone hypersecretion, predominantly caused by a somatotroph pituitary neuroendocrine tumor (PitNET). Acromegaly-causing tumors are histologically diverse. Our aim was to determine transcriptomic profiles of various somatotroph PitNETs and to evaluate clinical implication of differential gene expression. A total of 48 tumors were subjected to RNA sequencing, while expression of selected genes was assessed in 134 tumors with qRT-PCR. Whole-transcriptome analysis revealed three transcriptomic groups of somatotroph PitNETs. They differ in expression of numerous genes including those involved in growth hormone secretion and known prognostic genes. Transcriptomic subgroups can be distinguished by determining the expression of marker genes. Analysis of the entire cohort of patients confirmed differences between molecular subtypes of tumors. Transcriptomic group 1 includes ~20% of acromegaly patients with GNAS mutations-negative, mainly densely granulated tumors that co-express GIPR and NR5A1 (SF-1). SF-1 expression was verified with immunohistochemistry. Transcriptomic group 2 tumors are the most common (46%) and include mainly GNAS-mutated, densely granulated somatotroph and mixed PitNETs. They have a smaller size and express favorable prognosis-related genes. Transcriptomic group 3 includes predominantly sparsely granulated somatotroph PitNETs with low GNAS mutations frequency causing ~35% of acromegaly. Ghrelin signaling is implicated in their pathogenesis. They have an unfavorable gene expression profile and higher invasive growth rate.

show abstract

Section: Resultsmentioning

confidence: 99%

Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly

Rymuza

Kober

Rusetska

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…3B; Supplementary Table S10). Both Ga i and Ca 2þ signaling are previously connected to pituitary neoplasia (25,26). The inhibitory G protein subunit alpha I-2 (GNAI2; Ga i-2 ) and G protein subunit beta 1 (GNB1, Gb 1 ) were upregulated in Gsp þ tumors (Fig.…”

Section: Dna Methylationmentioning

confidence: 87%

“…Both of these signaling cascades are involved in the regulation of cAMP response. Inhibitory Ga i proteins most notably inhibit receptordependent cAMP synthesis (48) and CaCn signaling stimulates the cAMP response element-binding (CREB) protein, a main downstream target of mitogenic effect of cAMP (26,49,50). Thus, activated Ga i and downregulated CaCn may reflect the adaptive response to elevated cAMP levels caused by GNAS (Ga s ) mutation and prevent the excessive cellular proliferation in Gsp þ tumors.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Characterization of Growth Hormone–Secreting Pituitary Tumors

Välimäki

Schalin‐Jäntti

Karppinen

et al. 2019

Molecular Cancer Research

View full text Add to dashboard Cite

Somatic driver mechanisms of pituitary adenoma pathogenesis have remained incompletely characterized; apart from mutations in the stimulatory Ga protein (Ga s encoded by GNAS) causing activated cAMP synthesis, pathogenic variants are rarely found in growth hormone-secreting pituitary tumors (somatotropinomas). The purpose of the current work was to clarify how genetic and epigenetic alterations contribute to the development of somatotropinomas by conducting an integrated copy number alteration, whole-genome and bisulfite sequencing, and transcriptome analysis of 21 tumors. Somatic mutation burden was low, but somatotropinomas formed two subtypes associated with distinct aneuploidy rates and unique transcription profiles. Tumors with recurrent chromosome aneuploidy (CA) were GNAS mutation negative (Gsp À ). The chromosome stable (CS) -group contained Gsp þ somatotropinomas and two totally aneuploidy-free Gsp À tumors. Genes related to the mitotic G 1 -S-checkpoint transition were differentially expressed in CA-and CS-tumors, indicating difference in mitotic progression. Also, pituitary tumor transforming gene 1 (PTTG1), a regulator of sister chromatid segregation, showed abundant expression in CA-tumors. Moreover, somatotropinomas displayed distinct Gsp genotypespecific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory Ga (Ga i ) signaling is activated in Gsp þ tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in Gsp À somatotropinomas, whereas Gsp þ tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated Ga i signaling.Implications: These findings provide valuable new information about subtype-specific pituitary tumorigenesis and may help to elucidate the mechanisms of aneuploidy also in other tumor types.

show abstract

“…Higher expression of dopamine receptors DRD1 and DRD2 was in turn found in group 3. Irrespectively to receptor activation, Ca 2+ influx through voltage-gated Ca 2+ channels (VGCCs) also plays an important role in GH secretion (Nussinovitch, 2018). CACNA1C and CACNA1D encoding VGCCs were identified as expressed at significantly higher level in groups 1 and 2 as compared to group 3 (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic classification of pituitary neuroendocrine tumors causing acromegaly

Rymuza

Kober

Rusetska

et al. 2022

Preprint

View full text Add to dashboard Cite

Acromegaly results from growth hormone hypersecretion caused by somatotroph pituitary neuroendocrine tumor (PitNET). Our molecular profiling revealed that acromegaly-causing tumors form three distinct transcriptomic subgroups with different histological/clinical features. Transcriptomic subtypes of somatotroph tumors differ in the expression levels of numerous genes including those involved in hormone secretion and genes with known prognostic value. They can be distinguished by determining the expression of marker genes. Transcriptomic group 1 includes ~20% of acromegaly patients with GNAS mutations-negative, mainly densely granulated tumors with NR5A1 (SF-1) and GIPR co-expression. Group 2 tumors are the most common (46%) and include mainly GNAS-mutated, densely granulated somatotroph and mixed PitNETs. They have significantly smaller size and express favorable prognosis-related genes. Group 3 includes predominantly sparsely granulated somatotroph PitNETs with low GNAS mutations frequency causing ~35% of acromegaly cases. Ghrelin signaling is implied in their pathogenic mechanism, they have unfavorable gene expression profile, and invasive growth rate. Since a subgroup of somatotroph tumors have high NR5A1 expression, using SF-1 as classification marker specific to gonadotroph PitNETs could be reconsidered.

show abstract

Ca2+ Channels in Anterior Pituitary Somatotrophs: A Therapeutic Perspective

Cited by 5 publications

References 106 publications

Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly

Transcriptomic Classification of Pituitary Neuroendocrine Tumors Causing Acromegaly

Genetic and Epigenetic Characterization of Growth Hormone–Secreting Pituitary Tumors

Transcriptomic classification of pituitary neuroendocrine tumors causing acromegaly

Contact Info

Product

Resources

About