Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells
Multiple G1 regulatory elements control the androgen-dependent proliferation of prostatic carcinoma cells
复制标题
DOI：
10.1074/jbc.273.32.20213
复制
发表时间：
1998-08-07
影响因子：
4.8
通讯作者：
Cavenee, KK
中科院分区：
文献类型：
--
作者：
Knudsen, KE;Arden, KC;Cavenee, KK
前列腺上皮细胞和大多数原发前列腺癌的生长依赖于雄激素，但雄激素如何调控细胞增殖仍未解决。通过鲜为人知的机制，复发的肿瘤细胞逃避雄激素需求。我们利用雄激素依赖的前列腺肿瘤细胞来证明雄激素通过影响G(1)-S进展的特定方面来影响细胞周期。这些细胞的雄激素耗竭导致早期G(1)期停滞，其特征是细胞周期蛋白依赖的激酶活性降低，视网膜母细胞瘤肿瘤抑制蛋白(Rb)磷酸化不足，激酶活性的降低部分归因于特定的G(1)周期蛋白的减少和细胞周期蛋白依赖的激酶抑制物的交替调节，利用这一信息，我们开发了一种可靠的方法来评估特定的G(1)调节蛋白绕过这些控制并促进雄激素非依赖性生长的能力。正如预期的那样，RE的失活是细胞周期进展所必需的。令人惊讶的是，驱动RE磷酸化的G(1)周期蛋白的过度表达不足以促进雄激素非依赖性细胞周期进程。在没有雄激素的情况下，病毒癌蛋白的引入确实促进了G(1)-S的进展，这取决于它们隔离RE和相关蛋白的能力。这些结果首次证明，控制G(1)-S转变的多种因素决定了雄激素依赖的生长，雄激素非依赖性前列腺癌的形成可能是由于这些过程的错误调控。
Prostatic epithelial cells and most primary prostate tumors are dependent on androgen for growth, but how androgen regulates cellular proliferation remains unsolved. Using poorly understood mechanisms, recurrent tumor cells evade the androgen requirement. We utilized androgen-dependent prostatic tumor cells to demonstrate that androgen exerts its effect on the cell cycle by influencing specific aspects of G(1)-S progression. Androgen depletion of these cells results in early G(1) arrest, characterized by reduced cyclin dependent kinase activity, and underphosphorylated retinoblastoma tumor suppressor protein (RB), The reduction in kinase activity was partially attributed to reduction of specific G(1) cyclins and alternate regulation of cyclin-dependent kinase inhibitors, Using this information, we developed a reliable assay to assess the ability of specific G(1) regulatory proteins to circumvent these controls and promote androgen-independent growth. As expected, inactivation of RE was required for progression through the cell cycle. Surprisingly, overexpression of G(1) cyclins, which drives RE phosphorylation, was insufficient to promote androgen-independent cell cycle progression. Introduction of viral oncoproteins did promote G(1)-S progression in the absence of androgen, dependent on their ability to sequester RE and related proteins. These results provide the first evidence that multiple elements governing the G(1)-S transition dictate androgen-dependent growth, and the formation of androgen-independent prostatic tumors may be because of misregulation of these processes.