Use of mouse models to understand the molecular basis of tissue-specific tumorigenesis in the Carney complex
Use of mouse models to understand the molecular basis of tissue-specific tumorigenesis in the Carney complex
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DOI：
10.1111/j.1365-2796.2009.02114.x
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发表时间：
2009-07-01
影响因子：
11.1
通讯作者：
Kirschner, L. S.
中科院分区：
文献类型：
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作者：
Kirschner, L. S.
卡尼综合征（CNC）是一种常染色体显性遗传的多发性内分泌肿瘤综合征，由皮肤色素沉着、粘液瘤病、内分泌肿瘤和神经鞘瘤组成。大多数病例是由于PRKAR1A的失活突变，该基因编码3',5'-环腺苷单磷酸（cAMP）依赖性蛋白激酶PKA（蛋白激酶A）的1A型调控亚基。为了了解与PRKAR1A突变相关的肿瘤发生的分子基础，我们开发了常规和条件PRKAR1A敲除（KO）小鼠以及与这些基因操作相对应的原代细胞培养模型。在生化水平上，从细胞中去除Prkar1a会导致PKA活性增强，与从CNC患者分离的肿瘤中观察到的效果相同。Prkar1a突变杂合的小鼠（CNC患者的确切遗传模型）以预期的频率出生，并且易于肿瘤，在camp反应细胞类型（如雪旺细胞，成骨细胞和甲状腺细胞）中发展肿瘤。为了了解组织特异性肿瘤形成的基础，我们从三个不同的组织中创建了该基因的组织特异性KOs：神经嵴（雪旺细胞）、脑垂体和心脏。在神经嵴和垂体中，Prkar1a的消融导致过度增殖和肿瘤发生，而在发育中的心肌细胞中，同样的操作导致增殖减少和胚胎死亡。KO心脏也表现出黏液瘤变化，这表明PKA激活与黏液瘤形成之间存在联系，尽管这种关系的性质尚未确定。这项工作证实了Prkar1a作为组织特异性肿瘤抑制因子的作用，并且正在进行的工作集中在确定受PKA失调影响的关键下游信号靶点。
Carney complex (CNC) is an autosomal dominant, multiple endocrine neoplasia syndrome comprised of spotty skin pigmentation, myxomatosis, endocrine tumours and schwannomas. The majority of cases are due to inactivating mutations in PRKAR1A, the gene encoding the type 1A regulatory subunit of the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase, PKA (protein kinase A). In order to understand the molecular basis for tumorigenesis associated with PRKAR1A mutations, we have developed conventional and conditional Prkar1a knockout (KO) mice as well as primary cell culture models corresponding to these genetic manipulations. At the biochemical level, removal of Prkar1a from cells causes enhanced PKA activity, the same effect which has been observed in tumours isolated from CNC patients. Mice heterozygous for Prkar1a mutations (the exact genetic model for CNC patients) are born at expected frequencies and are tumour prone, developing neoplasms in cAMP-responsive cell types such as Schwann cells, osteoblasts and thyrocytes. In order to understand the basis of tissue-specific tumour formation, we have created tissue-specific KOs of the gene from three different tissues: the neural crest (Schwann cells), the pituitary gland and the heart. In the neural crest and the pituitary, ablation of Prkar1a leads to excess proliferation and tumorigenesis, whereas the same manipulation in developing cardiomyocytes leads to reduced proliferation and embryonic demise. The KO hearts also exhibit myxomatous changes suggesting a connection between PKA activation and myxomagenesis, although the nature of this relationship has not yet been determined. This work confirms the role of Prkar1a as a tissue-specific tumour suppressor, and ongoing work is focused on identifying the key downstream signalling targets affected by dysregulation of PKA.